Northwestern University

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY: Chronic lung allograft dysfunction (CLAD) is the primary driver of morbidity and mortality in lung transplant recipients. Currently there is a need to identify clinical and molecular biomarkers of CLAD, where the latter has the potential to inform targetable pathways for intervention. There is growing evidence to hypothesize that a key component of CLAD pathobiology is the recruitment of profibrotic monocyte-derived alveolar macrophages (MoAM) upon injury to the lung epithelium. Profibrotic MoAMs stimulate the activation, differentiation, and proliferation of myofibroblasts. With sustained injury, MoAMs are continually maintained through colony stimulating factor 1 (CSF1) signaling through its cognate receptor (CSF1R), leading to progressive fibrosis. T-regulatory cells dampen ongoing injury and have been shown to mitigate CLAD in preclinical models and are also associated with more favorable lung transplant outcomes in humans. Our group demonstrated that recipient-derived MoAMs express profibrotic genes in mice and humans and that administering a CSF1R antagonist improved fibrosis in a murine model of CLAD. Translating these findings in humans requires analyzing longitudinal data collected before CLAD diagnosis. Where most studies focus on measurements made at one or two points in time, often when CLAD has significantly progressed, the proposed work will leverage a machine learning approach developed by our group to determine clinical states and their sequences that develop after lung transplantation. This work will examine associations between these clinical states with flow cytometry, single cell and spatial transcriptomic analysis of BAL fluid across time to identify early, predictive indicators of CLAD. Specifically, the proposed work will address the hypothesis that the emergence of pathogenic MoAM and loss of tissue-resident donor-derived T-regs in serially sampled BAL predict CLAD and ACR respectively. Aim 1 will determine whether the CSF1-driven maintenance of profibrotic MoAMs precedes the clinical diagnosis of CLAD. Aim 2 will determine whether the paucity of tissue-resident donor-derived T-regs is associated with CLAD after ACR. Both aims consist of 1. Combining flow cytometry and single-cell transcriptomics to quantify cell abundances and ligand receptor analyses relevant to either aim unique to CLAD BAL and 2. Integrating these molecular features with clinical data in machine learning models for CLAD (aim 1) and ACR (aim 2) prediction. In leveraging these data-driven and machine learning approaches, the long term goal of the proposed work is to reveal therapeutic targets and elucidate early signs of ACR and CLAD for timelier intervention and to ultimately reduce lung transplant failure. The candidate and her mentors have designed a detailed training plan that utilizes the support of diverse mentors and resources in immunology, single-cell genomics, machine learning, and translational research. Ultimately, this training plan enables the candidate to develop the rigorous computational and scientific skills to become an independent physician scientist in the realm of biomedical machine learning and translational immunology.

NSF Awards · FY 2024 · 2024-09

The biggest stars can produce bright explosions like supernova or collapse into black holes. One important question is whether fresh fuel from the outer part of the star can get mixed into the center of the star, where it could burn, extending the life of the star. Observations of these stars suggest they live longer than might be expected, so some mixing must be occurring in the star. This work will model mixing in massive stars using computer simulations. The simulations will determine what fraction of the star gets mixed. These results will be used to make new predictions of the lifetimes of such stars, and they will be compared to observations. The results will also be used to predict how many supernova and black holes we expect to see. Each summer, this project will support high school students to complete independent research projects supervised by the project team. This award will support the Research Experience in Astronomy at CIERA for High school students program at Northwestern. This is a highly interactive three-week program that provides high school students experience with astronomy research in an atmosphere of team-style learning, hands-on training, and mentorship from professional scientists. Although rare, massive stars are disproportionately important in astrophysics. They are progenitors of neutron stars and black holes, and they chemically enrich their environments through winds and/or mass loss. Accurate stellar and population synthesis models of intermediate- and high-mass stars are required to robustly predict properties of stellar remnants and nucleosynthetic yields. The lives and deaths of these stars are intrinsically linked to mixing that occurs at the boundary of their convective cores. If fresh fuel can mix into the core, it can extend the star’s main-sequence lifetime and alter its subsequent evolution. Constraining convective boundary mixing is essential for accurate and robust neutron star and black hole population synthesis modeling. This investigator will derive convective boundary mixing parameterizations from multi-dimensional numerical simulations. The team will run a suite of three-dimensional global spherical numerical simulations to measure convective penetration. They will determine how convective penetration varies with stellar mass, age, and rotation rate. The parameterization of convective penetration will be implemented in the MESA code, and we will validate it by comparing to asteroseismic observations. Finally, they will use the new parameterization in the population synthesis code POSYDON to determine how our new parameterization affects compact object binary merger rates. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to understand the pathological mechanisms of sulfur mustard gas keratopathy (MGK) in the cornea. Sulfur mustard (SM) is an alkylating agent that has been used as a chemical warfare agent. SM exposure to the eye results in acute corneal injury. A subset of patients, particularly those with high exposure levels, develop chronic or delayed symptoms, which is known as MGK. Thus far, there are no specific treatments available to stop or reverse the detrimental effects of MGK. One of reasons for the lack of a specific treatment is that the mechanisms of MGK are not fully understood. Autophagy is a process by which cells break down and recycle their own cellular components, including damaged proteins and organelles. Even though autophagy has been recognized as a fundamental cellular process against stress, autophagy can play beneficial or detrimental roles depending on the context. In the cornea, it has been demonstrated that in response to most of stresses, autophagy plays beneficial roles to protect tissue homeostasis. Our laboratory and many other investigators have been focusing on such protective roles of autophagy in the cornea. However, the detrimental role of autophagy in the cornea has not been studied. Interestingly, when we investigated the role of autophagy in corneal injury due to chemical exposure, we found that nitrogen mustard (NM), an analog of sulfur mustard, induced a unique autophagy, which plays a harmful role in the cornea. It has been shown that the liberation of Beclin1, a key regulator in induction of autophagy, from Beclin1-Bcl2 complex can induce autophagy. Our preliminary data suggest that after NM exposure, sequestration of Beclin1 in Beclin1-Bcl2 complex attenuates NM-induced corneal inflammation. Therefore, we hypothesize that corneal mustard exposure induces autophagy via liberating Beclin1 from Beclin1-Bcl2 complex and such induced autophagy promotes corneal inflammation and contributes to MGK. In Aim 1, we will explore: (i) whether NM exposure will affect Beclin1-Bcl2 binding in vitro and in vivo; and (ii) whether manipulation of Beclin1-Bcl2 binding will affect NM-induced autophagy in cornea. In Aim 2, we will capitalize on our ability to conduct gain- and loss-of-function studies of induced autophagy in mice. We will inhibit induced autophagy via either reducing Beclin1 expression or preventing the disassociation of Beclin1-Bcl2 complex in vivo. We will also enhance induced autophagy via preventing the binding of Beclin1 and Bcl2 in vivo. We will utilize these genetically modified mouse models to determine whether the detrimental effects of NM exposure in cornea will be: (i) attenuated by inhibition of induced autophagy, while (ii) increased by enhancement of induced autophagy. Knowledge from this project will reveal the pathological importance of induced autophagy in corneal MGK and will form the foundation for the development of novel therapies for this disease by targeting this Beclin1-Bcl2 complex-regulated autophagy pathway.

NSF Awards · FY 2024 · 2024-09

The goal of the SuperCDMS Collaboration is to directly detect galactic dark matter and in so doing address the following questions: what is the particle nature of dark matter, what are its astrophysical properties, and how does it relate to the Standard Model? In pursuit of this goal, the Collaboration is nearing completion on the construction of a new experiment, SuperCDMS SNOLAB, sited in SNOLAB, Sudbury, Canada. The advanced cryogenic detectors being used by the experiment have unprecedented sensitivity to nuclear recoil interactions from dark matter with mass in the 400 MeV/c^2 to 6 GeV/c^2 range (the mass range from approximately an individual proton to a few protons), as well as inelastic electronic interactions in the 1 MeV/c^2 to 1 GeV/c^2 range (the mass range approximately between an electron and a proton.). The SuperCDMS SNOLAB experiment will have sensitivity to dark matter interactions down to a cross section where solar neutrino interactions with the detector become a limiting background (the so-called “neutrino fog”). The SuperCDMS collaboration, and the university groups supported by this award, will complete the installation of experiment during the first award year, and will subsequently transition to commissioning and data acquisition. As part of commissioning, it is our goal to establish stable, optimal detector operation and understand the detector response, including backgrounds. The tasks supported under this award will be scientific or involve those being scientifically trained. Those tasks are essential to producing timely results from the first run of the full payload. The work supported by this award will focus on: Completion and deployment of a robust, efficient, and fast data quality monitoring and data handling chain, providing personnel to support the installation and commissioning efforts of the SuperCDMS SNOLAB experiment, and producing a comprehensive detector response model including a plan to fully calibrate the SuperCDMS SNOLAB detectors. Finally, the supported work will include analysis of science data taken in the CUTE facility with a HV detector tower to produce competitive dark matter searches, as well as analysis of Run 1 data from the full SuperCDMS SNOLAB payload. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Intercellular adhesion is essential for tissue development and maintenance. One such adhesive structure is the zonula adherens junction (ZA) where the tension sensitive protein -catenin (cat) couples transmembrane cadherins to the actin cytoskeleton. While the essential function of ZA components is well-established, we know comparatively less about the dynamic regulation of this structure. During tissue morphogenesis, cells must accommodate neighbor exchanges while maintaining crucial barrier function. Here we address the overarching hypothesis that cat integrates actomyosin based mechanical signals with post-translational modification (i.e., phosphorylation) to control epithelial barrier structure and function. Our team has identified an evolutionarily-conserved phosphorylation scheme within a flexible region of cat linking the F-actin binding domain to its mechanosensitive middle-domain. Phosphorylation at these sites is required for strong cell-cell adhesion in widely used dog kidney epithelial cell line, as well as development in flies. But mechanistic underpinnings and critical contribution to mammalian development remain incompletely understood. We find that phospho-cat appears enriched at the zonula adherens junction and is reduced by actomyosin inhibition. We also find that a phospho-mimic form of cat phenocopies this ZA enrichment and adopts a more opened conformation in vitro. These data suggest actomyosin contractility promotes cat phosphorylation, leading to a conformational change that favors recruitment of a key binding partner required for cat junctional enrichment, ZA structure and barrier function. To address this model, Aim 1 will address whether Afadin, a multi-domain scaffold protein implicated in ZA structure, is a key effector of phospho-cat, making use of a newly mapped binding site in cat. Aim 2 will establish the in vivo relevance of this mechanism through characterization of a novel cat phospho-null mouse with postnatal developmental delay. Together, these aims will fill a fundamental gap in the understanding of how a central cell-cell adhesive component is regulated by mechanical and chemical modification to control epithelial barrier function, with implications for diseases caused by cat mutation, such as butterfly-shaped patterned eye dystrophy and vitreoretinopathy. I will carry out these research aims under the mentorship of my sponsor, Dr. Cara Gottardi, with her expertise in epithelial cell biology. Our strategy will be complemented by a training plan that enhances skill in quantitative image microscopy, methods to interrogate epithelial barrier function, and tissue-level phenotypic analysis in a mouse model. As these training goals are applicable to a range of research questions, they will be foundational to my career development as a physician scientist, with current interest in ophthalmology, given that cat missense mutations causally contribute to eye disease, and the mouse developed in Aim 2 may provide an avenue for future independent research.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Vibrio cholerae is a water-borne bacterial pathogen that causes the non-inflammatory diarrheal disease cholera. Millions of cholera cases each year imperil vulnerable populations, especially in areas of humanitarian crisis and regions of great poverty, highlighting an urgent need to expand our understanding of V. cholerae pathogenesis. One of the unique aspects of V. cholerae is its secreted Multifunctional-Autoprocessing Repeats-in-Toxin (MARTX) that contributes to the establishment and persistence of infection. After secretion, MARTX forms a pore in eukaryotic cell membranes to translocate its effector cassette into the host cytoplasm. There, the cysteine protease domain of MARTX releases multiple effectors that disrupt host signaling, cell structure, and endocytic trafficking. This proposal focuses on one effector called the actin crosslinking domain (ACD), which introduces iso-peptide bonds between globular-actin monomers leading to filamentous-actin dissociation and cytoskeletal collapse. ACD was recently found to promote activation of the mitogen-activated kinases (MAPK) and lead to the secretion of pro-inflammatory interleukins; however, how cells detect actin damage is unknown. This proposal seeks to determine the host signaling response to ACD and characterize its role in V. cholerae infection. Elucidating this signaling response will provide insights into both V. cholerae pathogenesis and cellular response to actin depolymerization; therefore, the goals of this project closely align with the mission of NIAID to better understand infectious diseases. Aim 1 seeks to determine the signaling downstream of actin crosslinking that leads to MAPK activation using inhibition and genetic knockdown strategies. Aim 2 seeks to define the impact of ACD on V. cholerae colonization and bacterial-stimulated host signaling using an adult mouse colonization model. The training received while completing the proposed work will be fantastic preparation for the career goal of the trainee to lead a lab studying host-pathogen interactions. Through this proposal, the trainee will gain: 1) expertise in defining host signaling responses to bacterial toxins with techniques such as retroviral transfection, siRNA knockdown, cell line development, and western blot; 2) skills in mouse infection experimentation to assess in vivo pathogenesis and signaling; and 3) other skills needed for academic research such as science communication, grant writing, and manuscript generation. Feinberg School of Medicine at Northwestern University provides an excellent environment to complete the proposed scientific aims and achieve build towards the career goals of this trainee. Dr. Karla Satchell sponsors this proposal as an expert in MARTX toxins and host responses. Her mentorship will provide the trainee thorough expertise in bacterial toxins and host-pathogen interactions. Also, weekly bacteriology journal club provides frequent opportunities for the trainee to present their science and new literature. Finally, the department and university have elite core facilities with expert consultants in techniques such as proteomics, mass spectrometry, imaging, and advanced sequencing.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Functional Magnetic Resonance Imaging (fMRI) has become a powerful tool for studying the underlying functional architecture of brain networks by tracking temporal correlations in the activity of different brain regions; a technique called resting-state functional connectivity (rs-FC). Recently, individualized methods of rs-FC have revealed reliable differences in functional organization between individuals and group averages that have been implicated with differences in behavior. These precision fMRI methods involve collecting extended amounts of rs-FC data across multiple sessions for each subject and the use of advanced denoising techniques to improve the quality of the data. Individual-specific networks have not been examined in older adults yet, even though group-average studies suggest that brain networks change systematically over the course of the lifespan and as a function of disease, both in cortical and cerebellar regions. I propose the use of a dataset of highly sampled older adults, ages 60-75 (N = 38), and younger adults, ages 18-30 (N = 38), to create individual-specific parcellations and network representations using high-quality anatomical and rs-FC data. In Aim 1, I will examine whether the properties of individualized networks in older adults differ compared to young adults. In Aim 2, I will examine whether the networks affected in Alzheimer’s Disease (AD) differ from those affected in healthy aging, particularly in the cerebellum. Preliminary data suggests that, with sufficient high-quality data, cortical networks in young adults are stable across days (r > 0.85), supporting their endophenotypic nature and potential for use as biomarkers. This study will be the first to use individualized measures in older adults to provide a better understanding of neurodevelopmental changes to rs-FC that may be relevant to behavior. Individualized network topology has previously been found to be predictive of behavioral and cognitive measurements, suggesting that it may be a promising avenue to search for biomarkers of cognitive decline. My pre-doctoral work (Aim 1) will set the benchmark for using precision fMRI with an older population to study the relationship between brain network variability and cognitive decline. My post-doctoral goal (Aim 2) is to apply these methodologies to the study of AD-related changes to the functional architecture of the brain and how these changes drive hallmark cognitive symptoms. This project will also provide ample opportunities for additional scientific and professional training. My training goals will focus on gaining theoretical and practical knowledge of defining individualized functional networks and brain parcellations, ensuring the quality of anatomical images using FreeSurfer, and applying special considerations to obtain reliable signal from cerebellar data. Professional development goals will center on mentoring practices and science communication. These skills will be key to my future career as an independent researcher dedicated to elucidating the relationship between individual differences in networks and cognitive changes in healthy and pathological aging and fostering diversity and inclusion in academia.

NIH Research Projects · FY 2026 · 2024-09

SUMMARY RAS signaling has been implicated in a wide spectrum of processes central to normal development and disease. Human mutations in RASA1 (a GAP negative regulator of RAS) are associated with capillary malformation-arteriovenous malformations (CM-AVM). These comprise a group of non-cancerous vascular lesions characterized by hyperproliferative endothelial cells that form abnormal and fragile blood vessels. CM- AVMs are underdiagnosed, but when identified in the clinic are often responsible for seizures, internal hemorrhage, and/or stroke. Germline mutations affecting one RASA1 allele alone are insufficient to give rise to vascular anomalies. For pathologic malformations to arise, additional somatic mutations are necessary. Open questions in the field include: 1) What are the secondary hits that trigger malformations in the context of RASA1 haploinsufficiency and, 2) How do the additional altered genes collaborate with RASA1 mutations to facilitate the emergence of abnormal vessels? Answers to these questions are needed to develop pharmacological interventions and to develop strategies to restore vascular homeostasis. Here we will use novel mouse models that reproduce AVMs in several organs to study the biological consequences of RASA1 loss. Preliminary experiments revealed that RASA1 is a critical regulator of endothelial cell-cell junctions and vascular integrity. In addition, we found that RASA1-haploinsufficiency in mice provides a sensitized genetic platform that can be used to interrogate the effect of potential second-hit targets. Genetic combinatorial effects can be tested, followed, and studied in a highly tractable murine ear assay. Based on our preliminary data, we hypothesize that RASA1 haploinsufficiency alters junctional complexes, and sensitizes endothelial cells to the emergence of vascular malformations. Two aims were developed to test this hypothesis: (1) To identify partners that synergize with RASA1 haploinsufficiency to promote the emergence of vascular malformations and, (2) To elucidate molecular targets that act downstream of RASA1 to promote junctional complex integrity and resist emergence of vascular anomalies. Mechanistic experiments will be performed with human cells and several mouse models. In addition, we will extend validation to human lesions through retrospective analysis of donor tissue. Clarifying the contribution of RASA1 to vascular homeostasis could offer an unprecedented opportunity for intervention by identifying the key players in this debilitating condition. In addition, understanding cooperating genes will improve screening protocols and benefit patients harboring RASA1 mutations who live with an elevated lifetime risk of complications from AVMs. The proposed studies will be directly applicable to the clinical setting of RAS- related malformations, as they will broaden our understanding of the disease and potentially aid in stratifying patients toward specific management paradigms.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Patients with severe pandemic SARS-CoV-2 pneumonia suffered damage of alveolar epithelial cells due to direct viral injury, subsequent immune response, and secondary bacterial pneumonia, which presents clinically as the acute respiratory distress syndrome (ARDS). Despite a similar severity of ARDS, some patients recover their lung function without sequelae, while others develop persistent respiratory symptoms and radiographic abnormalities, or progressive lung fibrosis resulting in death or requiring lung transplantation. The mechanisms driving the heterogeneous outcomes remain elusive. Mitochondrial dysfunction and metabolic changes are commonly observed in patients with severe pneumonia/ARDS and in patients with lung fibrosis but whether this dysfunction is causally related to failed epithelial repair after injury is not known. We focus on an intermediate epithelial cell population expressing genes characteristic of both alveolar epithelial type 2 (AT2) and type 1 (AT1) cells. These “transitional cells” are expanded during postnatal development and in several models of lung injury and fibrosis, and human fibrotic lungs. In our published and preliminary studies, we observed that mitochondrial complex I (MCI)-dependent NAD+ regeneration, independent of ATP synthesis, is necessary for postnatal alveologenesis. Rather than inducing a metabolic crisis and cell death, lung epithelial- specific deletion of NDUFS2, an essential MCI subunit protein, prevented AT2-to-AT1 differentiation resulting in a dramatic expansion of transitional cells and subsequent death of the animal from respiratory failure. Transitional cells lacking MCI function demonstrate activation of the integrated stress response (ISR) and a small molecule inhibitor of the ISR rescued the lethality of the knockout mice. I also observed that loss of NDUFS2 in adult AT2 cells leads to the spontaneous development of lung fibrosis and death of the animal from respiratory failure within several months, highlighting the potential importance of this pathway in lung fibrosis. Collectively, we hypothesize that the loss of MCI function increases the mitochondrial NADH/NAD+ ratio through a pathway that requires OMA1, DELE1, and HRI to activate the ISR and enhance ATF4-mediated transcription, precluding normal alveolar epithelial differentiation. I will test this hypothesis in the following two aims: Aim 1: To determine whether an increased mitochondrial NADH/NAD+ ratio and DELE1 are necessary for ISR activation that precludes AT2 to AT1 differentiation in the absence of mitochondrial complex I. Aim 2: To determine whether epithelial ATF4 activation is necessary and/or sufficient for impaired AT2 to AT1 differentiation. We propose causal experiments using sophisticated genetic murine models to link mitochondrial metabolism, activation of the ISR, and failed epithelial differentiation to the development of fibrosis. We pair our experiments with samples collected from patients with pulmonary fibrosis at the time of lung transplant, with a goal of credentialling mitochondrial metabolism and the ISR as targets for therapy to prevent and treat lung fibrosis.

NSF Awards · FY 2024 · 2024-09

A major goal of astronomers is to understand how galaxies grow and change throughout the history of the Universe. To help achieve this goal, the investigator and a graduate student will use a powerful new instrument on the Subaru Telescope to study galaxies during "Cosmic Afternoon." Cosmic Afternoon is a relatively recent period in the history of the Universe when galaxies stopped growing quickly and began to mature into the objects we see around us today. The team will measure a variety of galaxy properties and explore how these properties influence galaxy growth rates. They will also collaborate with data visualization experts to create a web-based tool for members of the public to explore the new observations and learn how astronomers use spectroscopy (the amount of light emitted at different colors) to learn about galaxies. Chicago-area high school educators will be invited to collaborate on developing research-based lesson plans as part of an ongoing Research Experiences for Teachers program at Northwestern University. The lead investigator will mentor the graduate student, and together they will mentor undergraduate research interns recruited to participate in various aspects of the project. The research program will leverage optical and near-infrared spectroscopic observations from an upcoming 130-night galaxy survey that will be conducted using the Subaru Prime Focus Spectrograph (PFS). Survey operations are scheduled to begin in early 2025 and will ultimately deliver rest-optical spectra of 240,000+ galaxies at z~0.5-1.5 (corresponding to lookback times of ~5-9 billion years). The investigator and her team will first use archival data to develop new photoionization model-based tools for measuring the physical conditions in the interstellar medium of emission-line galaxies from PFS and other intermediate-redshift surveys. These tools will then be used to analyze the first year of PFS data and investigate the chemical enrichment and abundance patterns in a representative sample of galaxies from this key period for the first time. The new model-based parameter estimation tool will be publicly distributed, and the abundance measurements will be included in value-added catalogs as part of the first PFS data release in 2027. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

This award combines novel detections of gravity waves and particles with traditional astronomy observations to better understand the physics of merging black holes and neutron stars. This way of exploring the universe is powerful but presents challenges. Often the direction and origin of the merger is uncertain, and astronomers must search large areas of the sky to identify any explosions that may be related. Response time is also important, as any astronomical signal may only last for hours and may be confused with many unrelated sources in the night sky. To address this challenge, a team led by the University of Arizona and Northwestern University will develop a tool that uses data archives and real-time observations to help astronomers assess incoming candidate counterparts to gravity wave and neutrino events. This product will lower the barrier to enter this exciting field and bring together communities including high schools, smaller institutions and amateur astronomers. This award will fund scholarships for high school students to conduct related research. The team will build the Treasure TROVE (a Tool for Rapid Object Vetting and Examination), which will use the vast stores of information in astronomical archives and real-time searches for supernovae to help multi-messenger astronomers assess and prioritize incoming candidate counterparts to gravitational wave events and neutrinos. For each candidate transient counterpart to a gravitational wave or particle messenger, the Treasure TROVE will crossmatch it with galaxy catalogs, archival imaging, and other public archives to determine whether the distance, variability, and association with other types of transients is consistent with the messenger. This will allow for ~50% of candidates to be discarded without any further need of follow-up, and for the most promising candidates to be prioritized. This program will involve community engagement, providing workshops, tutorials, and public workspaces that will ensure the broadest possible community can use the Treasure TROVE and participate in multi-messenger astronomy. Multi-messenger event localizations can span 1-1000s square degrees on the sky, and follow-up electromagnetic observations can uncover tens to hundreds of transients within that region - only one of which can be related to the gravitational wave, neutrino, or high-energy particle alert. The Treasure TROVE tool will take basic information of recent transients and automatically place each object in context using historical light curves and host galaxy identification, along with cross-matching with image archives and multiple point source, variable, and quasar catalogs. The Treasure TROVE will simplify this task with an easy-to-use software and web interface, optimizing follow-up telescope resources and speeding discovery. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Approximately 60% of hemiparetic stroke-survivors experience significant chronic motor deficits in their paretic upper limb, typically caused by damage to the corticospinal tract (CST). Alternative neural pathways, such as the cortico-reticulospinal tract (CRST), can be recruited to achieve movement of the affected arm and hand, but may have undesirable consequences. For example, the diffuse, bilateral branching of reticulospinal neurons can produce abnormal muscle co-activations (synergies) in the paretic limb, and involuntary mirror movements (associated reactions) between limbs. Together, these effects create stereotypical movement patterns post- stroke, and there is growing interest in novel "anti-synergy" interventions to enhance usage of residual CST systems rather than strengthening the CRST. Imaging has the potential to become an invaluable tool for evaluating whether rehabilitative strategies can preferentially access CST versus CRST pathways. However, current functional imaging research has focused on cortical activity, and must theoretically infer what pathway is used. Structural MRI can directly assess changes in white matter pathways, but it is limited to detecting long- term plasticity. To guide new interventions, there is a critical need to directly evaluate what descending motor pathways are active during specific movements. Thus, the overall objective of this study is to generate a novel fMRI dataset in participants with post-stroke hemiparesis, capturing neural activity during unilateral hand- grasping throughout the CST and CRST, and to evaluate differences when grasping with the paretic versus non- paretic hand. Our lab has developed advanced strategies to improve fMRI signal quality, but we show that large datasets per person are still needed to accurately localize and interpret activation patterns; this is challenging in stroke-survivors, who may fatigue quickly. Our innovative MRI-compatible hand-grip device provides supported, adjustable arm positioning and real-time force feedback, allowing us to reproduce a motor task across multiple sessions and generate sufficient data. In Aim 1, we acquire multi-echo fMRI data in the brain and brainstem; we hypothesize that increased reliance on the CRST will cause increased ipsilateral cortical and brainstem activation when grasping with the paretic limb, and that this will correlate with functional impairment (Upper-Extremity Fugl- Meyer Assessment). In Aim 2, we acquire fMRI data in the spinal cord; we hypothesize that grasping with the paretic hand will be associated with increased activation in more superior cord segments (intra-limb synergies) and grasping with the non-paretic hand will correspond to increased activation in the contralateral hemi-cord (associated reactions). We will also explore how neural activity correlates with individual EMG measures of muscle co-activation. This work is significant because it will provide direct evidence of descending motor pathway involvement in post-stroke hemiparesis, and demonstrate the utility of neuroimaging for identifying physical and pharmacological interventions to reduce reliance on CRST and drive more effective rehabilitation.

NIH Research Projects · FY 2025 · 2024-09

Leveraging our experience as a KL2 program, we submit this Northwestern University Clinical and Translational Sciences Institute (NUCATS) K12 application in conjunction with the NUCATS UM1, T32, and R25 applications. Through a needs assessment, brainstorming sessions, and interviews, we identified key challenges – translational science (TS) competency training that is a foundation for life-long learning and high impact research, including scientists from all relevant disciplines – and solutions, training innovations which we have started to implement in our KL2 and will expand in the proposed K12. Our overarching goal is to train and nurture clinical and translational scientists from varied fields to be resilient leaders of high-functioning, interdisciplinary teams, leaders well positioned to tackle translational roadblocks and procure external funding, and who employ implementation science (IS) principles and partner with affected/interested groups and end-users. We propose these specific aims: Aim 1) Provide K12 structure including communication, advisory support, oversight, and integration with the UM1 and T32 and other institutional training programs, to optimize effectiveness and efficiency of operations; Aim 2) Model interdisciplinary collaboration through dedicated Program Faculty to help fill gaps in Scholar mentoring and require all faculty to complete mentor training; Aim 3) Promote academic variation of applicants through (a) outreach across the institution to encourage applications from all departments at the Feinberg School of Medicine and relevant departments at other schools, to help to ensure that applicants and Scholars come from different areas and are working in varied stages of translation, and (b) K12 application support; Aim 4) Build an ESI Academy, a near-peer community of K12 Scholars and any K- or R-aspirer, including ESI Academy Socials and a seminar series with core and elective content for the Scholars; Aim 5) Personalize Scholar training using (a) a baseline assessment of TS and translational research competencies, (b) identification of the desired mastery level for each competency, and (c) an individualized training roadmap, using a novel tool – which we call COMPASS (Competency Assessment and Pathway Development) – to prioritize and monitor proficiency development; Aim 6) Provide enhanced approaches such as: (a) an active learner model with Scholars as PI of their training roadmap, (b) training that is non-siloed, i.e., delivered by cross-disciplinary mentors, (c) hybrid and online delivery, archived for efficient and timely Scholar use, and (d) leadership training including seminars and coaching; Aim 7) Evaluate the K12 Program using continuous improvement evaluation cycles to: (a) help to ensure that we are at the forefront of best practices and to position us to innovate, and (b) assess outcomes, using a priori designated metrics; Aim 8) Disseminate best practices and knowledge gains to our institution, the other Chicagoland CTSAs, the larger Chicagoland community, and the national CTSA consortium, including through a digital repository open to all and discoverable, hosted by NUCATS and the Galter Health Sciences Library.

NSF Awards · FY 2024 · 2024-09

As society increasingly relies on digital technologies, the growing energy consumption of computing systems makes their continued scaling unsustainable. At the same time, conventional computers face fundamental challenges in solving many important computing problems related to optimization. A possible solution to these challenges is to fundamentally change the architecture of computing systems. A promising example of such unconventional computing approaches is probabilistic (p-) computing, which uses a network of probabilistic bits that collectively evolve towards the network’s energy minima, which are designed to correspond to the solution(s) of the computing problem of interest. However, the realization of large-scale p-computers that provide computational advantage over conventional computers still requires improvements in the energy efficiency and speed of existing p-bits. This project will address this need by developing p-bits based on a new type of magnetic device, referred to as an antiferromagnetic tunnel junction. These devices have inherently faster dynamics than existing magnetic p-bits, making them excellent candidates for p-bit implementation. The project brings together experts in materials, devices, circuits, and architectures, who will co-design the proposed p-bits and explore domain-specific computing architectures that combine these p-bits with state-of-the-art semiconductor chip technology. The results of this project will impact a broad range of commercial markets, which face hard computational tasks related to combinatorial optimization. Applications of the developed domain-specific probabilistic computers can include logistics, transportation networks, wireless infrastructure, and chip design, to name a few. In addition, this project also contains educational components for semiconductor workforce development. These plans include collaborative development of a new course focusing on next-generation computing based on emerging materials. The project will also collaborate both with external professional societies as well as with local university resources, to provide opportunities for high school, undergraduate, and community college students to gain exposure to scientific research and training in magnetism and advanced computing. Through its combined research and workforce development efforts, the project will contribute to the continued leadership of the United States in the important areas of microelectronics technology, chip design, and advanced computing systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Background: Care fragmentation is a major challenge for older adults living with Alzheimer's Disease and Related Dementias (ADRD) and multimorbidity. Those in this population who are adversely affected by social determinants of health (SDoH) are particularly vulnerable to the negative outcomes associated with care fragmentation due to complex care needs, cognitive impairments, and social barriers. Care fragmentation is associated with medical errors, poor patient experience, billions of dollars in wasteful healthcare spending, and increased mortality. Although care coordination can mitigate care fragmentation and reduce social barriers associated with disparities in health outcomes, it demands collective efforts and interdependent relationships by clinicians across care teams and sites. Care coordination research has primarily focused on care tasks or components and standardized tools. The complex, dynamic, and interdependent relationships among clinicians through which care is delivered and coordinated have not been sufficiently evaluated. Approach: Based on my previous work, I propose that this gap be addressed using social network analysis (SNA) and electronic health record (EHR) data. Use of SNA and EHR data may better evaluate system- and patient-level clinician networks across settings and over time (during K99) and explicate how clinician networks relate to patients’ social context and health outcomes (during R00) for older adults with ADRD and multimorbidity. Specific Aim 1 will map the system-level clinician network for a cohort of over 90,000 older adults with multimorbidity, including ADRD, using a combination of structured and unstructured EHR data. Specific Aim 2 will detect and describe patient-level clinician networks for older adults with ADRD and identify characteristics of weak networks that could be associated with fragmented care. Specific Aim 3 will identify relational processes that are influenced by SDoH and contribute to disparities in health outcomes for older adults with ADRD. I hypothesize that patients more adversely affected by individual- and community-level SDoH are more likely to be cared for by clinicians in peripheral system positions, fragmented network structures, or networks weakening over time, and that having peripheral, fragmented, or weakening clinician networks will be associated with higher costs and risks for hospitalization and mortality. Mentoring and Training Plan: I will work with a highly interdisciplinary mentorship team of experts in data science, complex systems, health disparities, bioinformatics, health services and outcomes, computational social science, stakeholder engagement, primary care, ADRD, and aging research. My mentorship team will guide my training to gain competencies in longitudinal SNA and natural language processing during the K99. This K99/R00 award is vital for continuing my progress in achieving my career goal of establishing an independent, transdisciplinary research program to improve care coordination, thereby enhancing healthcare quality for older adults with multimorbidity, particularly those living with ADRD.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Distortion product otoacoustic emissions (DPOAE) are grossly underutilized in clinical applications. Yet the need for early and accurate diagnosis as well as monitoring of new therapies is growing and will demand more precise diagnostic tools. This proposal lays the foundation for assimilating advanced DPOAE diagnostics into clinical practice. Specifically, the first aim will validate the test performance of a new protocol for recording DP-Grams. This protocol will use frequency-specific stimulus conditions that are matched to local properties of the cochlea with the goal of better detection of mild-to-moderate hearing loss. The second aim will utilize DPOAE growth functions to detect early changes in the cochlea due to aging and differentiate these effects from those induced by over-exposure to noise. The third aim will use an innovative expansion of DPOAEs to objectively estimate cochlear tuning. The proposal will create a two-dimensional joint metric of tuning and DPOAE strength, which will help to identify hearing-related declines beyond mere changes in sensitivity. The proposed work also serves the critical need to extend the frequency bandwidth of all DPOAE applications to the highest frequencies of human hearing. This is made possible by incorporating modern calibration and signal delivery/recording techniques – developed in part by the laboratories of both PIs – into all experiments. The proposed experiments are built on previous peer-reviewed and published work from the two participating laboratories. Taken together, the proposed experiments are critical next steps necessary to move DPOAEs from a screening tool to potent clinical probe that serves the next generation of diagnostic and monitoring needs.

NSF Awards · FY 2024 · 2024-09

In today’s globalized societies, many conversations involve second-language speakers whose pronunciations typically exhibit a noticeable foreign accent. This project asks how foreign-accented speech varies across talkers from different first-language backgrounds and whether there are common features that characterize speech as foreign-accented across various languages. A detailed description of foreign-accented, or second-language, speech across individuals and across languages helps to develop strategies for overcoming miscommunications that can hinder conversations between humans from different language backgrounds and limit the effectiveness of human-computer voice interactions. This project also supports hands-on education for language sciences research. This project has two specific aims. The first aim develops a unique resource of digital speech recordings by both first-language and second-language speakers of multiple languages. Each speaker is recorded reading a carefully selected set of sentences and in both their first-language and their second-language. The recordings also include casual, spontaneous speech by each speaker in both of their languages. This unique set of recordings is fully documented, annotated, and made publicly available to encourage its use by researchers, speech technology developers, educators, and clinicians. In the second aim, the research potential of the digital speech resource is demonstrated through a series of acoustic analyses that develop a detailed and comprehensive acoustic characterization of first-language versus second-language speech across talkers and across languages. The analyses extend prior studies of variation in first-language and second-language speech that were challenged by the lack of parallel recordings in multiple languages. Collectively, this project yields a novel, publicly available digital speech resource and a set of analyses that can be leveraged for research and broader theorizing on both human and computer speech communication in multi-lingual settings. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Over prior funding cycles, the Northwestern University Clinical and Translational Sciences (NUCATS) Institute has developed and delivered a robust institutional infrastructure to support clinical and translational research. Our mature CTSA hub has made exceptional contributions to the consortium, attaining national prominence for igniting cross-disciplinary team science and boundary-crossing partnerships. These strengths now enable NUCATS to pivot and focus on clinical and translational science (CTS). This proposal addresses three of the most urgent and fundamental priorities to accelerate and catalyze translation: (a) improving the knowledge, skills and capacity of the translational science workforce; (b) accelerating discovery and development of innovations in interventions and processes to improve efficiency of translation; and (c) infusing implementation science (IS) methods into work across the translational continuum to increase the demand for and supply of effective health services to improve public health. NUCATS will develop, evaluate, and disseminate more effective health interventions to more patients more quickly through teamwork with our exceptional coalition of community, health system, and CTSA partners via three Specific Aims: IMPROVE, INNOVATE, and IMPLEMENT. For our IMPROVE Aim, we will expand and better educate our workforce, enhance partnering across our hub, and improve research participation that better enables generalizability of research results, thereby maximizing the beneficial impacts of translation on the health of all. For our INNOVATE Aim, we will catalyze innovation across all stages of the translational continuum to promote entrepreneurship as well as the rigor and reproducibility of translational research. For our IMPLEMENT Aim, we will infuse implementation science methods into clinical research across the translational continuum to accelerate public health impact. Each Specific Aim will be attained via a set of Strategies, which in turn consist of a set of Initiatives. Pursuit of the Specific Aims will be overseen by a highly interactive Multiple Principal Investigator (MPI) team ideally suited to provide strong oversight of the Specific Aims, with each MPI having primary oversight of one aim. The MPIs will tightly coordinate a team-based leadership structure emphasizing integration across hub and application components, supported by Advisory Committees. This proposal is further enabled by our renowned evaluation infrastructure, our longstanding leadership in open science principles (including Findable, Accessible, Interoperable, Reusable (FAIR) data) and our track record of leadership across the CTSA consortium. By the end of the proposed UM1, NUCATS will become a national champion and consortium resource for transdisciplinary research teams seeking to continuously improve CTS workforce performance to more efficiently deliver innovative and implementable solutions that improve health for all.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY This study will examine the contributions of socioeconomic status (SES) over the lifecourse to epigenetic age acceleration across adulthood. Numerous studies have established that age-related degenerative disease and mortality follow SES gradients. Early life SES has been shown to be associated with many markers of health across the lifecourse independent of SES in adulthood. This suggests that age-related decline is not simply the result of individual lifestyle decisions in adulthood but that it is also influenced by the socioeconomic conditions that individuals grow and develop within across the lifecourse. “Epigenetic clocks,” which measure various dimensions of biological aging using DNA methylation, hold promise to help describe healthy versus pathological aging. Epigenetic age acceleration, defined as having advanced estimated epigenetic clock age relative to one’s chronological age, is highly predictive of future age-related degenerative disease and mortality. Adding to well-documented socioeconomic gradients in biomarkers of inflammation, immunological function, and cardiovascular disease risk, recent studies have found that lower SES is associated with increased epigenetic age acceleration, particularly when using epigenetic clocks trained on clinical or phenotypic markers of aging. However, much of this evidence comes from studies using retrospective data on SES, which may be affected by recall and other biases. This study is innovative because it uses rich longitudinal data on SES measured prospectively over two decades among the mother and offspring participants in the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The CLHNS is an ongoing birth cohort study that has followed several thousand women and their children in Metropolitan Cebu, Philippines since 1983. Recent improvements in life expectancy in Cebu have corresponded to an increased public health burden of age-related disease and functional decline. DNA methylation data from blood samples collected in 2005 among both generations were used to measure epigenetic age acceleration from five epigenetic clocks shown to predict future health and aging in the CLHNS. This study addresses the following aims: 1) Estimate the total and direct associations between lifecourse SES measures and epigenetic age acceleration in young adulthood (for offspring) and middle adulthood (for mothers) and 2) In offspring, estimate associations between intergenerational educational attainment trajectories and epigenetic age acceleration. Training activities will focus on gaining skills in rigorous epidemiological methods for longitudinal exposures and mediation, including semiparametric methods that incorporate machine learning algorithms. Grounded in rigorous approaches from social epidemiology, this study will generate evidence to clarify the contributions of lifecourse SES to epigenetic aging across adulthood, while also identifying modifiable SES factors that may inform the design of interventions to reduce biological aging and age-related degenerative disease.

NIH Research Projects · FY 2025 · 2024-09

Project Summary. Schools are one of the most common settings where youth seek mental health services, yet existing school-based mental health interventions are often difficult to implement due to time, cost, and staffing limitations. There is a particular need for school-based interventions that target students with mild or moderate concerns (often called Tier 2 interventions) to address problems before they escalate and require intensive treatment. Digital, self-administered Single Session Interventions (SSIs) are evidence-based supports that are intentionally structured to deliver a clinically-meaningful dosage of evidence-based content within one session. Although multiple studies have found clinical effectiveness for school-based SSIs, there have been no systemic efforts to understand how SSIs can be practically implemented in schools as Tier 2 supports. In line with Objective 4.2 of the NIMH Strategic Plan, which aims to “expedite adoption, sustained implementation, and continuous improvement of evidence-based mental health services” this project aims to understand how evidence-based SSIs can be sustainably implemented in schools as Tier 2 supports, ultimately improving the likelihood of youth accessing mental health support. This proposal serves as a critical step in furthering the PI’s long-term goal of becoming an expert in the implementation of scalable school-based mental health interventions and pursuing an independently funded research career. Through this project, the PI will conduct focus groups (five groups, total n = 25-30) among community members (i.e., students, parents/caregivers, teachers, school administrators, and school mental health providers) to assess perceived facilitators and barriers to the effective implementation of evidence-based SSIs in schools (Aim 1). The PI will then work in partnership with community members (n = 10-15) to co-design multi-level implementation strategies (i.e., student-directed, staff-directed, system-directed) for increasing uptake and promoting sustainability of school-based SSIs (Aim 2). The proposed project is significant because it is the first to systematically investigate the real-world implementation of SSIs in schools. The completion of this project in combination with a training plan that consists of mentorship, coursework, and professional development activities will allow the PI to develop expertise deploying implementation science methods in school settings (Training Aim 1), strengthen skills in qualitative data collection and analysis (Training Aim 2), and develop expertise in Human Centered Design for co-creation of implementation strategies (Training Aim 3). The PI will be in an ideal training environment at Northwestern University to conduct this study and learn how to develop a robust program of research. With the mentorship of Dr. Jessica Schleider (Sponsor), Dr. Sara Becker (Co-Sponsor), and an expert consultant team, this study will launch the PI’s development as an independent implementation scientist.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Diabetic Retinopathy (DR) is the most common complication of diabetes and is the leading cause of vision loss in working-aged adults. DR is classified into non-proliferative DR and proliferative DR. In the non- proliferative stage, damage to retinal capillaries results in a lack of oxygen to the tissue. When capillary loss is significant, patients progress to the proliferative stage of disease, which is characterized by neovascularization, or growth of new blood vessels. These vessels do not function properly and cause bleeding into the retina and subsequent vision loss. While there are treatments for proliferative DR, there are none for non-proliferative DR, a stage at which vision loss could still be prevented for millions of patients. The lack of treatments is due to a lack of understanding of the underlying mechanisms that contribute to disease development. The literature demonstrates that inflammation may contribute to disease pathogenesis. C-chemokine ligand 2 (CCL2) is the most consistently elevated chemokine in intraocular patient samples from all stages of DR. Studies have also shown that leukostasis, or the firm attachment of leukocytes to the retinal vasculature, results in endothelial cell damage. However, there is a gap in knowledge in the field regarding how leukocytes promote capillary degeneration, which leukocytes are responsible, where this occurs, and which interactions between leukocytes and endothelial cells are necessary for DR pathogenesis. Investigating the inflammatory cascade beyond leukostasis could elucidate additional steps that can be targeted, reducing ischemia and thereby preventing vision loss from advanced disease. Based on the premise that static intravascular myeloid cells do not generally harm endothelial cells, but when they do (e.g. vasculitis) the damage is immediate and histologically obvious, our central hypothesis is CCR2-responsive myeloid cell transmigration is critical for DR progression, and blocking transmigration may prevent disease progression. We will test our hypothesis through two Specific Aims: (1) Determine whether and when blockade of CCL2-driven myeloid cell infiltration will halt the progression of inflammation in the mouse retina, and (2) Determine if blocking leukocyte-endothelial interactions early in the DR disease course can reduce DR progression. In Aim 1 we will use an acute model of inflammation induced by CCL2 intravitreal injections; in Aim 2 we will use a streptozotocin-induced diabetic mouse model. We will compare the effects of blocking leukocyte transmigration versus adhesion on DR progression, measured by markers of endothelial cell apoptosis, tight junction integrity, microglial activation, and leukostasis. We will adapt our intravital microscopy system to observe leukocyte dynamics in real time serially in the retinas of live mice with DR. The information obtained from this project will improve our understanding of the role of innate immunity on disease progression and aid in development of novel therapies for non-proliferative DR.

NSF Awards · FY 2024 · 2024-09

The work of the NSF Engineering Research Center for Human AugmentatioN via Dexterity (HAND) will lead to versatile, dexterous robotic arms and hands that address a broad range of human, industry, and societal needs. The purpose is to create robot manipulators that are widely useful “out of the box.” Today, robot arms become useful only after an expensive integration process, making them inaccessible to many who might benefit, including most of the country’s quarter-million Small and Medium Enterprises (SMEs). To be useful out of the box, robots must have truly versatile end-effectors (“hands”), AI-powered dexterous skills, and intuitive interfaces that trained workers can use immediately. Training must be widely accessible and career paths must be available to learners from a young age. Firms of all sizes must be able to adopt these robots, and workers of all education levels, high school through postgraduate, must be able to use them. The breadth and structure of the ERC program will enable HAND to address these technical, workforce, and ecosystem challenges, ultimately democratizing access to robot dexterity. Robots will no longer be limited to high-volume, highly repeatable operations; they will find application in low-volume high-mix manufacturing, food processing, remote handling of precious or dangerous materials, assistance for individuals with motor impairments, and many other areas. Widespread access to robotic manipulation will be vitally important as the U.S. addresses labor shortages in fields such as manufacturing and caregiving, and as demographics inexorably change, leading to a shrinking pool of workers supporting an aging population. While some areas of robotics have seen dramatic advances in recent years, dexterous manipulation has proven to be a more challenging problem, requiring a very high level of convergence. HAND will provide this with a Convergent Research program organized into three thrusts: Hands (sensing, actuation, design), Intelligent Dexterity (simulation, AI, control), and Human Interface (multimodal interface, programming, social/legal/industrial studies). The Center will bring together experts in materials, manufacturing, manipulation, soft robotics, artificial intelligence, machine perception, modeling, haptics, human-robot interaction, participatory design and research, team science, education, law, and the social sciences to overcome fundamental barriers to dexterity. These include achieving large scale integration of actuators and sensors, building robust visuo-tactile-motor skills that are composable into complex behaviors, and low-code programming by non-roboticists. The result will be an engineered system — hands, skills, interface, and training materials — that dramatically advances robotic manipulation and its accessibility. HAND’s dexterous manipulators will be where AI learns about the physical world, and where AI is transformed to useful physical work. Additionally, through Engineering Workforce Development efforts, HAND will provide a novel education platform for introducing learners to AI and dexterity; an accelerator program to help SMEs succeed with robots; REU and RET programs that increase access to STEM; and undergraduate and graduate certificates built on a foundation of dexterity, social impacts of automation, and participatory research and design methods. HAND will use those methods to engage potential users and ensure that the benefits of dexterity are widely shared. HAND’s Innovation Ecosystem will support strong engagement with small, medium, and large manufacturers, robotics companies, national labs, civic organizations, and educators via testbeds, advisory boards, a robust process for technology transfer, and a public interest initiative. Together with this ecosystem, HAND will impact the future of work by democratizing access to human augmentation via dexterity and framing the associated social, economic, and ethical implications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Cancer remains one of the leading causes of death worldwide despite advances in diagnoses and treatments. Immunomodulatory therapeutics like anti-PD-L1 and anti-PD1 enhance the host immune response against the tumor and have saved countless lives. However, these treatments only work a small fraction of the time. Immunosuppressive T-regulatory cells (Tregs) have come under scrutiny as the ratio of Tregs in the tumor microenvironment can dictate both clinical prognoses and whether a patient responds to immunotherapy treatment. Furthermore, current therapeutics to target Treg suppressive function, directly or indirectly, remain unspecific and transient with an extremely low efficacy. Therefore, new therapeutics need to be developed against Tregs and Treg suppressive function. Forkhead box protein 3 (FoxP3) is a Treg and Treg suppressive function specific target. FoxP3 is not only a lineage defining marker in Tregs, but also the master regulator of Treg differentiation and function. Given the role of FoxP3 as a transcription factor though, FoxP3 is known to be “notoriously undruggable” due to both its nuclear localization and lack of inhibitable binding pocket. Fortunately, our lab and others have shown chemically targeting the ubiquitin proteasome system (UPS) can regulate FoxP3 protein levels, and in turn, modulate Treg suppressive function. Unfortunately, UPS enzymes have wide substrate diversity and broad cell type expression, leading to off-target effects. However, through using small molecule compounds known as “molecular glues,” we can specifically glue FoxP3 with E3 ligases to promote its targeted proteasomal degradation. My preliminary data identifies and characterizes one lead small molecule compound as a FoxP3 degrader. First, using a FoxP3-GFP reporter system, 81 potential hits were identified from 640 small molecule library, which reduced FoxP3. Following a secondary dose-response screen, an additional screen by flow cytometry in human Treg-like MT-2 cells, and resynthesis of four potential lead compounds, one lead compound, termed MG03, was identified. MG03 was found to decrease FoxP3 in MT-2 cells as well as mouse primary Tregs, and my preliminary data suggests that MG03 promotes proteasomal degradation of FoxP3. Thus, the long-term goal of this proposed project is to further develop this lead compound to target Treg suppressive function in the context of cancer. The central hypothesis for this project is that Tregs can be targeted through FoxP3 by small molecular degraders to partially diminish Treg suppressive function and enhance the anti-tumor response. To test this hypothesis, we will address the following aims: Aim 1 will determine efficacy of the lead compound, MG03, in inducing FoxP3 degradation in vitro; Aim 2 will investigate the underlying mechanisms of MG03; and Aim 3 will evaluate efficacy of MG03 on Treg suppressive function in vitro and in vivo. This study will identify the first FoxP3-specific molecule glue to partially diminish Treg suppressive functions for cancer treatment.

NSF Awards · FY 2024 · 2024-09

Scientific teams are increasingly disrupting science by making pivotal discoveries and breakthroughs. These disruptive teams reshape established scientific paradigms and forge new ones, eclipsing established theories, methods, and research directions. Consequently, understanding the factors that foster disruptive scientific teams is essential for promoting new scientific paradigms, theories, methods, and avenues for future research. Previous research has documented the effects of team size, hierarchies, and distance among members on scientific disruption. However, the influence of gender composition on teams’ abilities to make disruptive discoveries and create new inventions remains underexplored. Drawing on previous research in gender composition and scientific disruption, the researchers aim to investigate the effects of gender composition on disruption and examine the causal mechanisms that could explain differences in its impact. This project encompasses three research goals. First, the project analyzes the impact of gender composition on disruption by examining more than 49 million papers and 4 million patents across different scientific fields over the last 50 years. The results yield empirical evidence of the impact of different gender compositions on scientific disruption. Second, the project conducts a laboratory experiment with 320 participants to understand the causal mechanisms that drive these effects. This experiment, which controls for gender composition, requires three-person teams to complete a disruption task that is designed for this experience and based on disruption research. Third, the project involves a massive survey and follow-up interviews with female scientists who have been part of disruptive teams to learn about their experiences and insights. This research promises to enhance understanding of the effects of different gender compositions on teams’ disruptiveness and contributions to science. The project highlights the theoretical and practical implications of specific team combinations in scientific research, giving institutions and funders information they can use as they reflect on the role of gender composition in scientific teams. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

In this proposal, we aim to address a critical challenge in lung transplantation: primary graft dysfunction (PGD), a severe complication impacting over half of all lung transplant recipients and have a particularly high incidence in those with pre-existing acute lung injuries (ALI) or acute respiratory distress syndrome (ARDS). Despite lung transplantation being a life-saving treatment for end-stage lung diseases, the high incidence of PGD significantly diminishes the long-term success and survival rates of these procedures. Our research is grounded in the discovery of the pivotal role played by intravascular nonclassical monocytes (NCM) in the donor lungs, which are activated by damage-associated molecular patterns (DAMPs), especially high mobility group box 1 (HMGB1), initiating the cascade leading to PGD. Building on this foundation, our proposal hypothesizes that receptor-interacting protein kinase 3 (RIPK3)- dependent necroptosis in both the recipient's native lungs and the donor lungs is a key driver of PGD. This hypothesis is supported by our preliminary data, which shows a sustained necroptotic process in the diseased lungs of recipients, particularly in cases of ALI and ARDS. We propose two specific aims to test this hypothesis: 1. Exploration of Autocrine Necroptosis in Recipient Lungs: The first aim focuses on the role of TNF-α induced autocrine necroptosis in monocyte-derived alveolar macrophages within the acutely injured native lungs. We plan to investigate the release of HMGB1 as a result of this necroptosis and how it contributes to the activation of donor-derived NCM during lung transplantation. This study will provide insights into the mechanisms through which pre-transplant lung conditions exacerbate the risk of PGD. 2. Investigation of Necroptosis in Donor Lungs: The second aim targets the necroptosis in donor lung tissue, specifically induced by mitochondrial reactive oxygen species (ROS) during the transplantation process. We aim to identify the cell populations in the lung responsible for mitochondrial ROS generation in response to ischemia-reperfusion injury and delineate their role in the necroptotic process within the graft. This understanding is crucial for developing targeted interventions to mitigate the risk of PGD arising from donor tissue conditions. The overarching goal of this research is to comprehensively understand and pharmacologically target the necroptotic pathways in both the donor and recipient lungs to reduce the incidence of PGD. This could positively impact the field of lung transplantation by significantly improving post-transplant outcomes. The successful completion of this research could lead to the development of novel therapeutic strategies and biomarkers for predicting and managing PGD, thereby enhancing patient survival and quality of life following lung transplantation.