Washington University

NIH Research Projects · FY 2025 · 2024-09

Conducting an accurate yet simple mathematical description of large-scale dynamical networks, such as biological networks, is an essential yet challenging step toward enabling design and control of such complex systems. The extraordinary growth of data-rich biology further calls for discovery of transformative mathematical techniques to facilitate data-driven research on dynamical systems. For example, daily rhythms in physiology allow organisms to anticipate reliable environmental events and adapt to changing environmental cues. The suprachiasmatic nucleus (SCN) generating these precise circadian oscillations and adapting to environmental changes is comprised of thousands of circadian neurons in the brain. The long-term goals of this research are to: 1) create a rigorous kernel method that generates a simple yet accurate representation for modeling complex nonlinear dynamical processes; 2) leverage this method to design interpretable and principled data-driven techniques for system control and learning of dynamic networks; 3) resolve longstanding biological questions about deciphering the underlying dynamics of coupled circadian clocks; and 4) identify enhanced environmental cues to produce desired behavior patterns such as chronotype setting and sleep consolidation. This proposal aims to overcome the significant mathematical challenges to solve important problems in circadian biology. In Aim 1, we will establish the moment kernel machine (MKM) that generates lossless compression models equivalent to the first-principles state-space models of dynamic network systems. In Aim 2, we will use the predictive power of MKM modeling to design signals that create desired synchronization patterns in oscillator networks. In Aim 3, we will demonstrate the versatility of the MKM technique with applications to circadian biology. This will involve dynamic learning of the SCN gene expression from measurements; and learning and shaping the output of SCN networks by designing dynamic light protocols for enforced biphasic sleep in young animals and consolidation of sleep fragmentation in aged animals, and assigning phases of entrainment (e.g., onset of daily activities) to animals of different genotypes and chronobiological properties. The integration of novel mathematical and biological tools will provide insight and guidelines for the theory- inspired experimental designs and lead to a comprehensive understanding of complex network behaviors such as coupled circadian oscillators producing daily patterns of sleep and wake.

NIH Research Projects · FY 2025 · 2024-09

The Innovative Network on the Science and Practice of Implementation, Research, and Engagement Center (INSPIRE) seeks to advance the science and practice of dissemination and implementation science research in low-to-middle income countries by adapting, scaling up, and sustaining evidence-based HIV interventions for adolescents and young adults (AYA). The Center offers a unique opportunity to conduct this paradigm-shifting work as part of the Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected adolescents in resource-constrained settings implementation science network (PATC3H-IN). Using an Appreciative Inquiry lens that focuses on the strengths within a system that fuels change, our mission is to serve as a hub for optimizing synergistic dissemination and implementation science research that appreciates, coordinates, and magnifies insights on adaptation, scalability, and sustainability with communities of interest from across the network via our Capacity Supporting Core (CSC), Advanced Methods and Modeling Core (AAMC), and Community Engagement and Dissemination Core (CEDC). Communities of interest in the six PATC3H-IN clinical research centers include researchers, implementers, community members, policymakers, and family members (especially guardians), friends, and adolescents and young adults (AYA). Our vision aligns with global goals to end the HIV epidemic among AYA. Our specific aims are: 1) Design and deliver cutting-edge implementation science training tailored to the needs of the HIV response to adolescents (Capacity Supporting Core); 2) Provide advanced methods and modeling expertise to combine an array of insights from the individual PATC3H-IN Clinical Research Centers (CRCs) together (Advanced Methods and Modeling Core); 3) Develop a shared strategy for community engagement and disseminating insights from PATC3H-IN to key communities of interest (Community Engagement and Dissemination Core); and 4) Evaluate INSPIRE progress and iteratively adapt, improve, and contribute to the network and science (Administration and Evaluation Unit). By creating a centralized mechanism to harness strength, listen, and convene across the networks, the INSPIRE Center will provide training, advanced methods, and engagement functions that will augment the findings of each CRC individual study across the HIV prevention and treatment care continuums, thus reducing disparities for AYA populations in LMIC settings and optimizing the translation of research findings into real-world impact.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY. The Vaccines and Therapeutic Antibodies to Respirovirus, Rubulavirus, Peribunyavirus and Phenuivirus (R2P2) ReVAMPP Center will utilize both well-defined and novel approaches to develop prototype vaccines and human monoclonal antibody (mAb)-based treatments for rapid response to viruses from the Paramyxoviridae, Peribunyaviridae and Phleboviridae families. R2P2 is composed of four primary Research Projects: two that collectively focus on prototype viruses of the Paramyxoviridae family including human parainfluenza viruses 3 and 1 (HPIV3, HPIV1), and human and bat mumps virus (MuV, BatMuV); and two that focus on prototype viruses of the Bunyavirales order including the Peribunyaviridae Oropouche (OROV) and La Crosse (LACV) and the Phenuiviridae Rift Valley Fever virus (RVFV) and Toscana virus (TOSV). Each project in R2P2 follows a parallel structure and makes use of the principles of reverse vaccinology, where insights from the structural and function studies will provide a framework to understand the molecular correlates of immunity and antigenicity and provide a roadmap for designing optimized immunogens. The foundational studies carried out in this ReVAMPP center will fill gaps in basic understanding of viral entry and will also inform how to extend the stabilization approaches successfully used to advance vaccines against agents with Class I fusogens (e.g., RSV), to those with Class II. A key R2P2 feature is that all four projects compare the same three vaccine platforms: protein subunit, mRNA, and chimeric VSV, allowing for cross comparisons that will rapidly yield information about platform performance in translating to related pathogens. The questions of which antigen stabilization paradigms, and which vaccine platforms are most amenable to generalizing from the prototype pathogens will be answered in depth and breadth by these comparisons across virus families. We assembled a collaborative team of world-renowned experts on viral envelope protein structure and function, leading immunologists, vaccinologists with extensive experience in industry and regulatory issues, and industry partners (e.g., Modena, GSK). The inclusion of junior investigators with exceptional promise is designed to ensure the engagement of the next generation of leaders in viral glycoprotein biology, viral immunology and vaccinology in pandemic preparedness. These Projects are served by an Administrative Core (Core A), a Data Management Core (Core B), and three Scientific Cores that perform structural biology, biophysics and protein engineering (Core C), antibody isolation and assessment (Core D), and correlates of immune protection (Core E) experiments in collaboration with multiple projects. The knowledge accumulated in this project and the robustness of the approaches implemented to develop prototype vaccines will be expanded to different viruses of the same families to evaluate their potential and broad applicability against emerging viruses of the Bunyavirales order and Paramyxoviridae family.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Obsessive-compulsive disorder (OCD) is characterized by intrusive, distressing thoughts (i.e., obsessions) and repetitive behaviors (i.e., compulsions) and is associated with significant functional impairment. Despite established first-line treatments, non-remission and relapse rates following treatment are high (e.g., ~50%), suggesting the existence of unidentified and untreated mechanisms in OCD. Prior work linking delayed circadian rhythms to OCD suggests this may be one such mechanism and represent a novel treatment target. Light therapy is a behavioral treatment that advances circadian rhythms and has been shown to be effective for reducing symptoms of disorders that are phenomenologically similar to OCD (i.e., posttraumatic stress disorder; Tourette’s disorder). Light is the primary zeitgeber, or environmental time cue, of human circadian rhythms, and light exposure also has direct effects on brain regions implicated in psychopathology. However, no study to date has tested the efficacy of light therapy for OCD. This project will address this gap in the literature by comparing the efficacy of light therapy (n=20) versus placebo light therapy (n=20) for OCD symptom reduction in adults with OCD+delayed bedtimes and examining change in circadian phase as a mechanism. We will also examine photic sensitivity and habitual light exposure patterns in adults with OCD+delayed bedtimes compared to healthy controls (n=25). Participants will complete 2 weeks of baseline sleep and OCD symptom monitoring followed by a baseline dim light melatonin onset (DLMO) and photic sensitivity assessment. Participants will then be randomly assigned to the active or placebo treatment condition and complete 5 weeks of treatment. OCD symptoms and DLMO will be reassessed at the end of treatment. We will examine whether OCD symptoms improve in the active treatment condition compared to the placebo treatment condition and whether change in symptoms is associated with advanced circadian phase. We will also examine whether adults with OCD+delayed bedtimes exhibit heightened light sensitivity and maladaptive habitual light exposure patterns (lower daytime, higher evening light). Results from this study will inform whether delayed circadian rhythms can be targeted for OCD symptom reduction. Through this project, I will complete transdisciplinary training in clinical trials in circadian medicine, advanced methods in light measurement and photic sensitivity, longitudinal modeling, and professional development, service, and scientific writing. This project will also provide me with preliminary data to be competitive for an R01 to facilitate my transition to independence.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Hibernation is one of the most remarkable physiological traits observed across a spectrum of animal species. Hibernating mammals reside primarily in a state known as torpor, characterized by lowered metabolism and reduced body temperature to conserve energy and survive harsh conditions. This natural phenomenon has inspired the concept of artificial hibernation (AH), which seeks to mimic the reduction in metabolism and body temperature using artificial means. Hypometabolism induced by AH in humans has the promise to impact broad medical domains, including enhancing survival rates during critical health events such as stroke and heart attacks, inhibiting the proliferation of cancer cells, extending the viability of organs for transplantation, and promoting longevity. However, noninvasive and safe induction of AH has remained within the realm of science fiction. My group recently discovered that stimulating specific neurons in the hypothalamus using ultrasound could noninvasively, safely, and reversibly reduce metabolism and body temperature in mice. We found this effect was associated with ultrasound-sensitive ion channels in torpor-associated neurons in the hypothalamus. While mice naturally enter torpor under food deprivation and cold exposure, we showed the feasibility of inducing AH through ultrasound in non-hibernating rats. Building on these promising discoveries, we propose the audacious hypothesis that neural pathways critical for metabolism regulation are conserved across mammals and can be activated by ultrasound. Our overarching goal is to pioneer a platform technique that harnesses ultrasound for the noninvasive and safe induction of AH, thereby catalyzing disruptive medical innovations. To achieve this ambitious goal, we will utilize an interdisciplinary approach that combines ultrasound engineering, system neuroscience, physiology, molecular biology, brain functional imaging, and behavior assays to address three pivotal questions: 1) What are the molecular, cellular, neural circuit, and system-level mechanisms that underpin ultrasound-induced AH in mice and rats? 2) How effective is ultrasound-induced AH in treating stroke, as demonstrated using rat stroke models? 3) Is the technique translatable to non-human primates as a critical step toward human application? Our proposed research program is innovative because it is expected to offer a disruptive technique to induce AH, provide an unprecedented opportunity to elucidate the complex role of the nervous system in metabolism regulation, pioneer the evaluation of ultrasound-induced AH in diseased models, and tackle the pivotal question of AH feasibility in humans. If successful, this high-risk, high-reward project could redefine the landscape of metabolism research and revolutionize the therapeutic manipulation of metabolic states. It could provide compelling evidence for the clinical translation of ultrasound-induced AH and turn what was once a science- fiction concept into medical reality.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT - OVERALL The SARS-CoV-2 pandemic highlighted the urgent need for better understanding of the mechanisms controlling broadly protective immune responses to rapidly evolving viral pathogens and generating vaccine candidates able to elicit such responses. The Washington University Cooperative Center on Human Immunology (WashU- CCHI) application (Mechanisms of Immune Protection Against Respiratory Viruses) proposes a comprehensive research plan towards two main goals: (a) defining the mechanisms of germinal center persistence after vaccination in humans and how germinal center dynamics impact engagement of de novo B cells and generation of robust CD4+ T cell, long-lived memory B cell, and bone marrow plasma cell responses (Project 1); (b) determining the functional caliber of systemic and mucosal immune responses to vaccines and infection and how these impact durability, breadth, and protection (Project 2). Three Cores will synergize with the two research projects to support the successful completion of the research aims. The Administrative Core (Core A) will manage the consortium, coordinate cross-project activities, and create the structure and environment needed to accomplish WashU-CCHI’s goals. The Clinical Core (Core B) will provide the clinical and statistical expertise to support the design and conduct of the human subjects’ research studies conducted under Projects 1 and 2. The Proteomics Core (Core C) will capitalize on an array of unique technologies for the interrogation of the circulating antibody protein and B cell repertoires in samples collected under Projects 1 and 2. The integrated and synergistic activities across these Projects and Cores will drive the successful completion of the WashU-CCHI’s ambitious research agenda, enabling achievement of our long-term goals of providing key insights on human immune responses and informing evaluation of new mucosal vaccines targeting the human respiratory tract against existing and emerging respiratory viral pathogens.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Research on the social dynamics of social media use in preteen girls is scarce, yet crucial: suicidal thoughts and depression have significantly increased among preteen girls in recent years, and this deterioration of mental health coincides with changes in social media use. Our conceptual model highlights two potential factors that may make preteen girls more susceptible to the negative effects of specific social media experiences: rejection sensitivity and pubertal timing. Online rejection experiences, overt and perceived, are a key component of preteen girls’ social media use that impacts mental health; however, these have not been directly quantified, particularly among those high in rejection sensitivity. Early puberty may be a window of vulnerability to the negative effects of social media use in girls, given the link between early puberty, depression, bullying, and social struggles. To address this, we propose a longitudinal study to examine the bidirectional relations between preteen girls' mental health and social media experiences, exploring psychological and developmental risk factors that strengthen – as well as mitigate – these relationships. This study will recruit a community sample of 250 girls, ages 10-11 years at baseline, to assess their mental health, social media use, rejection sensitivity, and hormone levels over three annual assessments (final age 12-13 years). The study will be the first to include microEMA (8x per day for 14 days, collected via smartwatch) and daily diaries (14 days) to assess preteen girls’ social media use. This approach offers an unparalleled examination of social media engagement, encompassing not only frequency and duration, but also how social media is used in daily life: the temporal unfolding of activities, mood, and social connection and rejection experiences that occur during social media use on a day-to-day basis. Weekly saliva samples will be collected across this period to assess global levels of puberty-related hormones as well as whether weekly hormonal fluctuations are linked to social media use and/or rejection sensitivity. In laboratory clinical interviews, questionnaires, and neural indices of rejection and acceptance sensitivity (EEG) will complement the social media measures. The overarching aim of this study is to examine the relationships between preteen girls' mental health and social media experiences, assessing whether high rejection sensitivity, and puberty impact these relationships; the protective effects of social connection on SM and neural response to acceptance will also be examined. Tests of the hypotheses within each of the aims will be performed through a series multi-level (also known as mixed effects) regression models, including growth models which incorporate time in the study as a variable. Through a detailed and focused assessment of how social media engagement unfolds over time, we will be able to highlight key turning points where elements of problematic social media use commence and persist, leading to the onset or maintenance of psychopathology. These elements of problematic social media use could inform media use guidelines and be future targets for intervention and prevention, particularly in those who may be sensitive to rejection and/or more advanced in pubertal development.

NIH Research Projects · FY 2024 · 2024-09

Project Summary/Abstract This S10 High-End Instrumentation grant application from Washington University (WU) in St. Louis requests funds in partial support of the purchase of a Bruker 15.2-Tesla small-animal MRI scanner to replace a two- decades-old Agilent/Varian 11.74-Tesla pumped MRI. This 11.74-Tesla MRI consumes a significant amount of liquid helium (5500 liters annually with a cost of over $150,000), which is unsustainable given the worldwide helium supply shortage. Moreover, with Agilent/Varian's exit from the MR market, the 11.74-Tesla scanner’s outdated hardware and software no longer meet the current and future needs of pre-clinical MRI research. The requested ultra-high field Bruker 15.2-Tesla Small-Animal MRI Scanner has state-of-the-art RF coils, gradient systems, and an extensive MR pulse sequence library to perform most modern MRI experiments in a preclinical setting. Its ultra-high field strength will provide a 2.6-fold increase in signal-to-noise ratio (SNR) compared to the 9.4T MRI, our only modern preclinical MRI system. In conjunction with its high-performance gradients (1.5 times stronger, almost 2 times higher slew rate than our 9.4T system), this gain can be leveraged to provide increased spatial resolution for ultra-fine anatomical definition, more accurate voxel-wise estimation of signal amplitude, increased blood oxygenation level-dependent (BOLD) contrast in functional MRI, and sensitivity to susceptibility weighted imaging and iron nanoparticles. This SNR gain is especially crucial for X- nucleus MR. Hydrogen and X-nucleus MR spectroscopy further benefits from increased spectral dispersion at a higher field. Of equal importance, advances in magnet technology allow the new 15.2-Tesla magnet to consume only ~12% as much liquid helium as the 11.74-Tesla system being replaced, thereby improving the sustainability of our preclinical imaging program. The requested Bruker 15.2-Tesla scanner will be managed by the Mallinckrodt Institute of Radiology’s (MIR) Small-Animal MR Facility. The Facility is service-oriented, highly collaborative, and well-integrated into the Washington University biomedical research community. The small animal MR facility is one of Washington University's most successfully shared research resources. In the five years preceding the pandemic, the Facility logged an average of approximately 5,900 scanner-usage hours annually from three small-animal MRI scanners. This scanner will help advance our already robust NIH-funded imaging research programs across many departments and centers in the School of Medicine and the McKelvey School of Engineering. University-wide support for this 15.2-Tesla small animal program has been provided by the Radiology Chair, Deans of the Schools of Medicine and Engineering, and Department Chairs and Center Directors of Major Users, with a total institutional commitment of $4,669,072.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Type 1 diabetes (T1D) is the second most common disease of childhood which results in substantial morbidity and mortality. This autoimmune disease is characterized by the infiltration of CD4 and CD8 T cells into the islets of Langerhans in the pancreas, where they ultimately deplete insulin-secreting  cells. Recent studies have shown that conventional type 1 dendritic cells (cDC1) are required for the development of Type 1 diabetes in the murine NOD model, which has many parallels to human disease. cDC1 are unique in their ability to efficiently cross-present  cell antigens to and prime autoreactive CD8 T cells. Furthermore, cDC1 are potent producers of IL-12 and may facilitate Th1 differentiation of CD4 T cells. A therapy that specifically eliminates cDC1 may therefore be expected to prevent the development of T1D by blocking autoreactive CD4 Th1 development as well as the presentation of self-antigens to autoreactive CD8 T cells. Our preliminary data show that a chimeric antigen receptor (CAR) T cell targeting XCR1, a chemokine receptor expressed by cDC1, is successful in depleting cDC1 in the spleen and pancreatic lymph node of NOD mice. Furthermore, cDC1 depletion by this CAR T cell also successfully inhibited the proliferation of a cDC1 dependent, self-reactive CD4 T cell in vivo. Thus, the central premise of this proposal is that XCL1 CAR T cells may be useful for the prevention of T1D. To address this, we will assess the ability of this CAR to prevent diabetes in NOD mice. Experiments proposed in Aim 1 will validate the specificity of the CAR for cDC1s and address the durability of cDC1 depletion in vivo. Aim 2 will assess the functional effects of cDC1 depletion by CAR T cells on autoimmune diabetes by assessing CD4 and CD8 T cell numbers and phenotypes within the islets as well as the rate of spontaneous diabetes incidence in NOD mice. Collectively, these studies may lead to the development of a novel preventative treatment for human Type 1 diabetes and establish a paradigm for CAR T cell mediated immunomodulation via selective targeting of DC subsets.

NIH Research Projects · FY 2025 · 2024-09

Antibiotic use is linked to increased risk for the onset or relapse of inflammatory arthritis, including rheumatoid arthritis and juvenile idiopathic arthritis, but the underlying basis for this and the gut-joint axis in regulation of both inflammatory and viral arthritis are not well understood. The goal of this proposal is to define how antibiotic mediated gut dysbiosis and loss of certain short chain fatty acids (SCFA)-producing bacteria alters local responses in the gut and distal inflammation in the joint. Heterogeneity of tissue resident synovial macrophages and fibroblasts have been described in rheumatoid arthritis but little is known about the cellular context and it has been virtually unexplored in the context of viral arthritis. I hypothesize the antibiotic-mediated gut dysbiosis and associated loss of certain SCFA-producing bacteria alters local intestinal epithelial responses to increase gut permeability and the priming of systemic pro-inflammatory responses. Furthermore, I hypothesize that this is linked to altered epigenetic and transcriptional programs in resident synovial cell populations that enhance synovial inflammation and worsen arthritis severity. Additionally, I propose that supplementation with exogenous SCFA can regulate these changes to temper the severity of arthritis. Using a combination of functional studies and sequencing technologies including high resolution spatial transcriptomics and ATAC-sequencing, this proposal will address gaps in knowledge related to how SCFA-producing bacteria shape intestinal epithelial cell responses to modulate the severity of viral arthritis (Aim 1) and how antibiotic-mediated gut dysbiosis affects tissue resident synovial macrophages and fibroblasts to enhance inflammation in Chikungunya viral arthritis (Aim 2). The elucidation of altered pathways may stimulate novel therapeutic approaches for modulation of gut dysbiosis and improved clinical management of viral and inflammatory arthritis. This proposal describes a 5-year training and mentorship plan to prepare the PI, Fang Roseanne Zhao, M.D., Ph.D., to become an independent physician-scientist principal investigator. The aims of the mentored research project described provide the framework for Dr. Zhao obtain additional expertise in gut immunology, synovial cell profiling, next generation sequencing, and bioinformatic skillsets to effectively study the complexity of the microbiome and gut-joint link. Washington University School of Medicine is an ideal training environment with a longstanding commitment to the training of physician-scientists, outstanding resources, expertise to complete the proposed research. During the 5-year period of support provided by this K08 award, Dr. Zhao will continue her career development through relevant coursework, collaborative learning, and mentors to allow her to obtain foundational knowledge and transition to her own independent research program as a successful physician scientist studying modulation of arthritis by the host-microbiome interface. *

NIH Research Projects · FY 2025 · 2024-09

Program Objectives and Goals: This proposal aims to provide recent college graduates with an intensive two-year mentored research experience in diabetes, endocrinology, and metabolism, and tailored professional development coursework to successfully guide scholars through the graduate school application process and ensure their success in completing a research-focused biomedical degree program (Ph.D. or MD/PhD). Through our proposed recruitment efforts and multi-layered mentoring approach, this proposal will build and enhance the biomedical research workforce in NIDDK mission areas by focusing on strengthening the research excellence of program scholars. Program Design: This program is designed for college graduates who have graduated within 36 months prior to the start of the program and are not currently enrolled in a degree program. Eight scholars in total will participate in the program. In year 1, we will recruit four scholars for two years of intensive training in biomedical diabetes, endocrinology, and metabolism research and professional development by leveraging the robust physical, administrative, and educational infrastructure and resources available at WashU. In year 3, an additional four scholars will be recruited to participate in the program. Our Program Directors (PDs) have an extensive collaboration record in designing, organizing, and recruiting for diabetes, endocrinology, and metabolism-related trainee programs. They lead highly successful summer and year-round programs for undergraduate and graduate scholars at WashU to support long-term research pathways. We will use data-driven recruitment strategies and will leverage our strong relationships in the field of endocrinology and metabolic disorders to recruit scholars into the program. The Research Training Plan will include: 1) State-of the-art, structured, yet individualized research training by performing diabetes, endocrinology, and metabolism-related scientific projects; 2) Personalized selection of seminars, workshops, and coursework for scholars to develop skills necessary for acceptance and completion of top-tier doctoral degree programs and expertise in diabetes, endocrinology, and metabolism research; and 3) Engagement with other WashU post-bac and graduate-level scholars.

NIH Research Projects · FY 2026 · 2024-09

PROJECT ABSTRACT Sensory over-responsivity (SOR), or strong negative reactions to and avoidance of innocuous sensory stimuli, affects about one in five school-age children and about two-thirds of children with autism spectrum disorder (ASD) and several other common neurodevelopmental disorders. Children with SOR experience considerable short- and long-term distress and impairment including fear and anxiety, poor sleep and nutrition, isolating social difficulties, and increased risk of mental illness. The cost of SOR in childhood is compounded by its disruption of developmentally appropriate social and situational experiences and its deleterious effects on family functioning. Despite its prevalence and impact on health and wellbeing, the causes of SOR are poorly understood and existing treatment approaches have met with limited success. Identifying the specific neural mechanisms that are disrupted in SOR could provide insights into its etiology and suggest promising approaches for developing effective interventions. Studies of typical sensory processing have revealed basic neural mechanisms that promote adaptive sensory responses, highlighting a powerful new translational approach to investigating the neural bases of SOR. The goal of this K99/R00 Pathway to Independence Award is to provide the applicant with the training needed to test if these neural mechanisms are disrupted in children with SOR and to support her continued success as an independent investigator. To achieve this goal, the applicant has assembled a committee of exceptional mentors and experts who will provide her with training in clinical presentations and assessments of ASD and SOR (Drs. Constantino, Sylvester, Green, and Pruett), administering functional MRI scans to children with and without ASD and SOR (Drs. Green, Sylvester, Dapretto, Pruett, and Dosenbach), applying multilevel models to complex datasets (Dr. Jackson), and developing skills for success as an independent investigator at a major research institution (all committee members). The proposed training will allow the applicant to test predictions about the relationship between one neural mechanism (suppression) and SOR in children using existing data and to pilot a functional MRI task to assess a second neural mechanism (surprise) in children during the K99 phase. Results from this work will inform the R00 phase, which will entail testing whether three neural mechanisms (adaptation, suppression, and surprise) are attenuated in sensory and fronto-limbic brain areas of children with SOR, both with and without ASD. This innovative research approach will clarify whether predictive mechanisms are disrupted in children with SOR and localize disruptions to specific brain areas, advancing scientific understanding of SOR and highlighting promising targets for interventions to be tested in a R01. Collectively, the proposed training and research will provide the applicant with the data, tools, and skills needed to launch a successful career at a top-tier research institution.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Crohn’s disease (CD) pathogenesis includes gene-environment interactions. GWAS have identified >100 CD susceptibility genes. Among the CD susceptibility genes, LRRK2 is of particular interest. It is associated with autophagy regulation and is also a Parkinson disease (PD) susceptibility gene. The same LRRK2 single nucleotide polymorphisms (SNPs) that increase susceptibility to PD and CD (G2019S, N2081D) result in LRRK2 kinase hyperactivity. This is of clinical relevance, as LRRK2-targeted therapies are being developed for PD. Understanding how LRRK2 hyperactivity contribute to CD pathogenesis will broaden therapeutic options for CD. We find that in the gut, LRRK2 is expressed predominantly in phagocytes (e.g., macrophages) instead of epithelial cells. We also find that in hosts without LRRK2 risk SNPs, LRRK2 kinase can be activated by gene-environment interactions involving autophagy gene SNP (ATG16L1 T300A) and cigarette smoking. We previously showed that such T300A-smoking interaction results in functional defects of small intestinal Paneth cells, an epithelial cell type with innate immune function. We find that CD patients harboring LRRK2 risk SNPs, Lrrk2 G2019S mice, and T300A-smoked mice are all prone to develop Paneth cell defects, and this is driven by macrophage LRRK2 hyperactivity. Our data suggests a key role of macrophage LRRK2 kinase activity in gut inflammation. The critical questions that need to be addressed before translating these findings to clinic include how LRRK2 kinase is activated in hosts without LRRK2 SNPs, and whether additional CD susceptibility genes contribute to macrophage LRRK2 kinase hyperactivity. Our long-term goal is to provide mechanistic insight and therapeutic strategies for CD patients. The central hypothesis is that macrophage LRRK2 kinase activity is critical in epithelial homeostasis. Our rationale is that identification of the mechanism(s) to restore proper macrophage LRRK2 levels will offer new therapeutic opportunities for CD. Our specific aims will test the following hypotheses: (1) autophagy deficiency sensitizes macrophages to increased reactive oxygen species production upon cigarette smoking, which then activates LRRK2 kinase; (2) additional CD susceptibility genes also contribute to LRRK2 kinase activation. This contribution is significant since it will establish LRRK2 kinase as a CD therapeutic target. The proposed research is innovative because we investigate how LRRK2 kinase activity is central to maintaining gut homeostasis, a heretofore-unexamined process. We also use state-of-the- art air-liquid interface culture and spatial transcriptomics to identify molecular and cellular targets that affect macrophage LRRK2 kinase activities. Identifying the mechanisms of how LRRK2 regulates a key disease- relevant phenotype will provide insight into other inflammatory disorders.

NSF Awards · FY 2024 · 2024-09

Nontechnical Description: Information technology has established itself as the cornerstone of modern society, underpinned by sophisticated semiconductor hardware with various functionality. To address the electrical bottleneck in integrated electronics, photonics-based scenarios have showcased unprecedented strengths in broadband, high-speed, and low-loss information processing and communications. However, conventional strategies relying on single material platforms encounter varying limitations in device performance and multifunctionality from their fundamental material shortcomings. A versatile platform for heterogeneous integration of different functional optical materials is not only a driving engine to prototype novel high-performance integrated photonic applications for information society, but also essential to investigate diverse nanophotonic physics such as the interplay between electromagnetic waves and other physical fields. We here propose the photonic van der Waals (vdW) integration on a library of distinct functional materials to infuse novel device functionalities established photonic platforms that were previously impossible to realize via single optical material. This includes the vdW integration of electro-optical (EO) material (barium titanate, BTO), cobalt ferrite (CFO), and III-V thin films (GaN) as gain or piezoelectric materials to Si and SiN photonics for high-performance and multifunctional integrated photonic circuits, providing a new paradigm for novel hetero-integration strategy to advance semiconductor technology, and explore nanoscale photonic phenomena such as Pockels EO modulation, mechanical-optical effects, lasing, and nonlinear physics. Technical Description: The hetero-integration of different optical materials, in contrast, can inspire record-setting devices and offer richer design freedom. Conventional hetero-integration approaches rely on hetero-epitaxy, limited by rigorous lattice matching and processing compatibility constraints. The photonic vdW integration thus permits versatile hetero-integration of diverse nanomembranes for vast applications with 3 significant breakthroughs: (1) Proposed layer transfer technique enables the vdW integration of dissimilar single-crystalline functional materials to arbitrary prefabricated photonic templates with excellent quality, which is previously not achievable via conventional heteroepitaxy methods. (2) The vdW integration concept is further extended to handling novel 3D materials for constructing novel vdW integrated photonic layouts to study nanophotonic coupling between light and other physical fields. (3) A universal platform to integrate multiple functional materials to a single photonic chip. We plan to vdW integrate BTO, GaN, and cobalt ferrite to Si and silicon nitride (SiN) photonics to develop high-performance integrated EO modulators, on-chip photodetectors, and isolators, as well as multi-materials co-integrated photonic chip covering key functionalities of optical modulations and photodetections for optical communication applications. BTO and cobalt ferrite will be grown by pulsed laser deposition (PLD) for epitaxial lift-off. Single-crystal GaN will be prepared by remote epitaxy via molecular beam epitaxy with 2D-materials-assisted layer transfer (2DLT) technique. Mach-Zehnder interferometers, ring resonators, and other dielectric waveguides structures will be fabricated in cleanroom for layer transfer. Optical measurements will be performed to confirm device performance with the following goals. (1) Kinetic study on new material epitaxy scenarios and the interplay of various photonic coupling. (2) Verify a new solution for high-quality thin film materials lift-off and hetero-integration, solving the lattice matching constraints in conventional hetero-integration methods. (3) Applying novel EO material of BTO (with among highest Pockels coefficient) for efficient EO applications. This study will advance semiconductor technologies and promote academic research on photonics integration and nanophotonic physics. 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 This study will develop a process to return Alzheimer Disease (AD) biomarker research results and will evaluate whether the results can be sent directly to participants in a safe and understandable way. The brain changes associated with AD begin decades before symptom onset during a stage called preclinical AD. Until recently, obtaining a diagnosis of preclinical AD was based on invasive biomarker tests (PET scans and lumbar punctures) only available at specialty research centers and not recommended for clinical use due to the lack of actionability and ethical concerns about the harms of disclosure. This landscape has dramatically changed with two new developments: a blood-based biomarker test is now available that can identify preclinical AD, and the first drug treatment directly targeting AD brain pathology received FDA approval in July 2023 for those with AD brain pathology and very mild symptoms. Medications targeting AD brain pathology are now being tested in individuals with preclinical AD because data suggest this is when they are most effective, signaling a future where asymptomatic individuals undergo AD biomarker testing prior to obtaining treatment, dramatically increasing the number of individuals who would be clinically tested and treated. Further, new regulatory requirements of the 21st Century Cures Act require immediate electronic release of clinical results, bypassing traditional clinician-mediated disclosure of AD biomarker results. Despite a current lack of clinical actionability for returning results related to preclinical AD, a recent participant Bill of Rights advocates returning AD biomarker research results to respect autonomy and because research results have personal value. Studies suggest that disclosure of AD biomarker results has no major psychosocial harms but have been limited to highly selected research participants in controlled research settings with in-person disclosure by specialized clinicians. This leaves significant gaps in knowledge and a lack of generalizability – a challenge for AD research more broadly that must be rectified. In a large, community-dwelling cohort of cognitively normal older adults, this study will develop a culturally- appropriate process for return of AD biomarker research results (Aim 1) and will evaluate whether the results can be sent directly to participants in a safe and understandable way using a randomized non-inferiority trial (Aim 2) with a sequential explanatory qualitative evaluation of experiences (Aim 3). This project responds to the rapidly evolving landscape where a readily available AD diagnostic blood test followed by a treatment is becoming a reality. The data produced will inform whether sending AD biomarker results directly to older adults can effectively communicate the results in a safe way, which will be necessary for widespread AD diagnostic testing.

NIH Research Projects · FY 2025 · 2024-09

Project Summary / Abstract This project will develop a novel molecular imaging technology that combines positron emission tomography (PET) and ultrasound (US) imaging to enable interactive PET and US scanning with real-time visualization of molecular contrast fused with US images. The motivation is to support an unmet clinical need of optimization of personalized patient therapy. Ultrasound imaging is widely used for tissue biopsy. The biopsied tissue samples permits molecular phenotyping and genotyping in order to better understand the pathobiology and to identify druggable target(s) in diseased tissues to tailor the therapeutical regimen. Although the US-buided biopsy is the current practice, its accuracy can be further improved by incorporating the PET tracer signal localization within the target lesions. The proposed technology builds upon a compact PET device that incorporates a robotic arm to interactively scan a patient to acquire images from any organ-of-interest. Fast image reconstruction engine will enable real- time visualization of molecularly targeting agents in organ/lesion for therapy optimization in individualized precision medicine. An unique advantage of this technology is that it combines a compact PET device with any existing clinical US scanner to enable the proposed PET/US imaging capability. These features will support interventions such as image-guided biopsy by overcoming the hurdle due to the size and cost of clinical PET scanners. The outcome of this effort is a new class of compact molecular imaging (MI) technology that can provide anatomic images, physiologic functions (such as speed of blood flow using Doppler US), and molecularly targeted information for a wide range of point-of-care imaging applications. The real-time PET/US imaging capability will disrupt the status quo and stimulate new applications of novel MI agents and MI-guided interventions, analogous to the invention of PET/CT that completely revolutionized the clinical utility of PET. Importantly, the cost of such system will be a fraction of a clinical PET/CT or PET/MR, making it the most affordable hybrid molecular imaging device for deploying novel applications. Thus the proposed technology development will address current unmet clinical needs and make long lasting scientific and societal impacts for years to come.

NSF Awards · FY 2024 · 2024-09

Photosynthesis is the engine of life on Earth, with photosynthetic organisms such as cyanobacteria, algae, and plants playing a pivotal role in harnessing solar energy for generating vital resources to sustain life on Earth. Among these organisms, a type of cyanobacteria called Anabaena 33047 stands out for its ability to produce extracellular polysaccharide (EPS), a substance that can be turned into fibers, providing a renewable alternative to synthetic fibers like nylon or polyester, commonly derived from petroleum. This project aims to deepen our understanding and improve the production of these natural fibers, which are not only environmentally friendly but also hold the potential to revolutionize the textile industry. By doing so, it addresses urgent global challenges such as pollution and resource depletion, promising significant societal benefits by offering sustainable material options and fostering international scientific collaboration. This project will also create broader impacts to engage individuals through research dissemination, social media, and workshops. Cyanobacterium, Anabaena 33047, is adept at producing and secreting large amounts of extracellular polysaccharide (EPS). Our preliminary studies have shown that EPS produced by Anabaena 33047 can be processed into strong fibers, offering a sustainable alternative to petroleum-derived fibers. Despite such potential, the intricate processes of cyanobacterial EPS biosynthesis, export, and regulation remain underexplored. Using a combination of systems biology and synthetic biology approaches, this project aims to identify and manipulate the genetic and metabolic factors that control EPS production. This will enable the tuning of EPS properties to enhance fiber strength and stretchability for industrial applications. The methodology involves creating models of EPS biosynthesis, testing various genetic modifications in Anabaena 33047, and systematically analyzing the resulting changes in EPS composition and fiber properties. Through this scientific inquiry, the project aims to lay the groundwork for scalable, sustainable production methods for biodegradable fibers, aligning with environmental goals and advancing bioengineering applications. This project is supported by the Systems and Synthetic Biology Cluster of the Division of Molecular and Cellular Biosciences. This collaborative US/India project is supported by the US National Science Foundation (NSF) and the Indian Department of Biotechnology (DBT), where NSF funds the US investigator and DBT funds the partners in India. 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 project will develop theory and methods to address network-level uncertainty in the control of large-scale networked systems. In such systems, the communication topology is described by a directed graph, whose nodes represent the agents in the system and the edges represent the communication links between them. To meet the modelling demands of realistic multi-agent settings, it is known that one needs to account for process and observation noise. The goal of this project is to explore what lies beyond these requirements and account for uncertainty at the level of the communication topology. To this end, the project will integrate the fields of random graph theory, and particularly graphon theory, with structural system theory to develop the needed theoretical tools to model and understand network-level uncertainty in control systems. Graphons are relatively new models in the landscape of random graph theory. They generalize many existing random graph models, such as the Erdös-Rényi model, by allowing for heterogeneous edge densities. A major research goal of this project is to characterize completely how a given structural system property behaves under network uncertainty. The main research problem of the project is the following: Given a desired system property (e.g., controllability and stability), what is the probability that a graph sampled from a graphon can sustain the property? The problem is by nature combinatorial and probabilistic. To tackle these challenges, this project will rely on tools from analysis and geometry to develop a new set of ideas geared toward the computation the aforementioned probabilities in the asymptotic regime, where the size of the random graph goes to infinity. The intellectual merits of this project lie in the use of methods from graphon theory, probability, and combinatorics to understand control system properties. More specifically, the project will (1) formulate new problems at the intersection of structural system theory and graphon theory, (2) develop a new toolbox for analyzing structural properties for network systems drawn from graphons, and (3) establish new theoretical results and algorithms that may have impacts on both areas and beyond. A major novelty of the proposed approach is that the project leverages tenets from graphon theory to circumvent the complexity of combinatorial problems, leading to the use of analytical tools and geometric approaches to provide complete solutions. 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

Abstract This proposal leverages a new interdisciplinary collaboration between Drs. Guoyan Zhao and Erik Musiek to define the transcriptional control of astrocyte identities, reactivities, and their roles in in Alzheimer disease (AD) and Parkinson disease (PD) pathogenesis. AD and PD are heterogeneous, multifactorial disease that selectively affects certain regions of the brain. Astrocytes are a major glial cell type in the central nervous system that play critical roles in neural circuit function and brain homeostasis. Accumulating evidence supports astrocyte as a major contributor of the neurodegenerative processes in AD and AD Related Dementias (AD/ADRD). In our recently published work, we identified three evolutionarily conserved astrocyte subpopulations which had unique marker gene expressions shared by the corresponding populations across multiple brain regions and different disease conditions. However, astrocytes do exhibit regional differences and transcriptomic changes in disease conditions linked to amyloid pathology, tauopathy, neuronal death, and neurodegenerative diseases, suggesting that astrocytes may contribute to regional differences in disease susceptibility. From this work, we have identified ten candidate TFs that exhibited regional differential expression patterns in human astrocytes whose expressions were dysregulated in disease conditions. Furthermore, these TFs are either known AD risk genes or have known functions in regulating cell activation or inflammatory response in cell types other than astrocyte. In this proposal, we will use our established in vitro and in vivo mouse experimental systems and the cutting-edge technologies of spatial transcriptomics and scRNA-seq to systematically evaluate each candidate TF in regulating astrocyte property and AD/PD pathogenesis. In Aim 1, we will perform in vitro experimental investigation of candidate TFs in regulating astrocyte property and neurodegenerative disease pathogenesis. We will manipulate candidate TF expression in primary murine astrocyte-enriched cultures properties of astrocyte with and without TF manipulation, astrocyte cultures to sustain growth of mouse cortical and human astrocytes cell line assess the including morphological changes, the ability of neurons, cytokine/chemokine expression, and and phagocytosis capability. In Aim 2 we will perform MERSCOPE spatial transcriptomic analysis to assess region- specific expression of candidate TFs. In Aim 3 we will perform in vivo gene knock-down and overexpression analyses to assess the function of candidate TFs in regulating astrocyte reactivity, neurodegenerative disease pathology, and the impact on other cell types. If funded and successfully implemented this proposal will provide validated TFs that regulate astrocyte activation and/or AD/PD pathology relevant to human disease pathogenesis. These TFs are excellent candidate targets for the development of effective AD or PD treatment strategies.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Earlier gains in reducing prostate cancer (PCa) mortality, partially due to advances in screening and the use of androgen deprivation therapy to treat metastatic PCa (mPCa), have not been sustained in recent years. Current clinical and research challenges include overtreatment of patients with low probability of progression, no effective therapy for metastatic castration-resistant PCa (mCRPC), and the persistent health disparities in PCa for African American men. A better understanding of the molecular dynamics and interactions among cancer and non-cancer cells within the tumor microenvironment CTME) at high resolution and in a spatial context across time will be crucial for addressing these challenges. Against the backdrop of recent advances in multi-omics and spatial technologies, we propose to use our expertise in the latest technological platforms, experience in atlas building, and strengths in PCa research and treatment at Washington University School of Medicine (WUSM) to extend our prior HTAN work to PCa. The proposed Human Prostate Tumor Atlas Center (HPTAC) will elucidate PCa architecture, cellular dynamics, TME interactions, and temporal evolution via the building of a molecularly resolved spatial atlas that integrates multi-omics, imaging, and clinical data, with a focus on spatial characterization with maximum optical display of molecular and cellular features. We will procure both retrospective and prospective PCa specimens with detailed clinical data at WUSM, which maintains a comprehensive repository of PCa specimens and has a high PCa patient volume (Aim 1). These specimens will span two critical transitions: from indolent to aggressive PCa and from hormone-sensitive to castration-resistant metastatic PCa. The high percentage of African American patients in our PCa patient population permits a 50% composition of African American specimens to investigate the biological basis for disparities associated with African ancestry. Aim 2 concentrates on molecular and spatial characterization of PCa specimens. At the core of the spatial characterization are spatial-omics, including sequencing-based (Visium/Curio Seeker) and imaging-based (Xenium/CosMx) platforms, 2D/3D imaging modalities, including CODEX, 3D in vitro Light Sheet Fluorescence Microscopy, and in vivo MRI/DBSI imaging. These technologies will be augmented by bulk and single cell omics for mutations/ancestry detection and overall molecular profiling. In Aim 3, data will be analyzed and integrated into a molecularly resolved spatial atlas of PCa. Co-registration, reconstruction, and integration will be achieved by employing computational tools, such as PASTE2, Morph, Mushroom. The resulting atlas will describe molecular, cellular, and spatiotemporal relationships of cellular and non-cellular components of the PCa ecosystem across critical transitions. In Aim 4, we will establish a collaborative infrastructure within our HPTAC and foster collaborations across HTAN centers. Data will be deposited with the HTAN Data Coordination Center in accordance with FAIR standards. Methodologies developed in, and findings from this study will have broad impact on atlas building for other cancers and on addressing some of the most pressing challenges in PCa.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Therapeutic restoration of protein function is a key goal for many neurodevelopmental disorders (NDDs) caused by genetic haploinsufficiency. MYT1L syndrome is a recently identified, understudied NDD caused by heterozygous loss of function mutations in the MYT1L gene, characterized by global developmental delay, particularly in motor and language development, intellectual disability, highly penetrant obesity and hypotonia, and a significant comorbidity of autism spectrum disorder (ASD) and/or attention-deficit/hyperactivity disorder (ADHD). Mice and human neurons with a MYT1L stop-gain mutation only show ~30% decreased transcript and protein levels, yet display profound cellular, molecular, and behavioral anomalies, indicating that MYT1L levels need to be tightly controlled for normal function. However, it is unknown how MYT1L levels are regulated. Understanding this regulation is a key step to identifying clinically relevant strategies for upregulating MYT1L as a therapy for MYT1L syndrome. An emerging protein upregulation strategy is to use antisense oligonucleotides (ASOs) to block elements that normally destabilize mRNA. Thus, ASOs could be used to increase protein expression from the mRNA of the remaining healthy allele. MYT1L has a conserved and longer than average 3’ untranslated region (UTR), which contains many regulatory elements responsible for transcript stability and translation efficiency, properties critical for protein synthesis. Using bioinformatic analyses, existing microRNA (miRNA) binding data, and a preliminary screen for active regulatory elements using a massively parallel reporter assay (MPRA), we have identified regions that may reduce stability of MYT1L transcripts, which I have therefore termed MYT1L Negative Regulatory Elements (MNREs), and discovered several candidate ASOs that increase expression. MNREs contain several predicted miRNA response elements (MRE) and Pumilio (PUM) response elements (PRE), which both induce translational repression or transcript degradation. This project seeks to study MYT1L post- transcriptional regulation (PTR) and its potential to be harnessed in translational therapies like ASOs for MYT1L syndrome. Aim 1 will test the importance of specific MRE and PRE sequences in MYT1L mRNA stability and screen for additional MNREs using an MPRA in iPSC-derived neurons to capture PTR in an appropriate cellular context. ASOs will both be used as tools and potentially be deliverables. Aim 2 will test the efficacy of a candidate ASO targeting a conserved MRE in restoring MYT1L protein levels in MYT1L haploinsufficient mice and rescuing associated transcriptomic and behavioral phenotypes. These findings will begin to explore MYT1L PTR and provide clinically relevant insights for rescue of MYT1L haploinsufficiency by direct targeting of MYT1L. This project will also provide the applicant the opportunity to train in RNA therapeutics, computational genomics, animal behavior to prepare for a future career as a physician-scientist studying neurogenetic disorders.

NSF Awards · FY 2024 · 2024-09

Safety is a critical property of autonomous systems such as driverless cars, unmanned aerial vehicles (UAVs), surgical robots, and energy systems. Naturally occurring faults and deliberate attacks may lead to safety violations, for example, Global Positioning System (GPS) denial attacks that cause vehicles to crash into pedestrians, or disabled actuators that leave a robotic arm stuck in an unsafe position. This award supports research that enables the development of a framework for safe control in the presence of sensor and actuator faults and attacks, thereby promoting the progress of science, advancing prosperity and welfare, and securing the national defense. This approach combines techniques from control theory, machine learning, and system security to enable provable guarantees across a wide range of autonomous systems and fault/attack scenarios. The developed techniques will be especially valuable for learning-enabled systems, which are known to experience severe performance and safety degradations when they encounter situations (such as deliberate attacks) that did not occur in their training data. This timely effort will enhance safety and trust, and hence pave the way for widespread deployment, of autonomous and learning-enabled systems across a variety of application domains. Beyond technical advancements, this project emphasizes a variety of education and outreach activities including course modules on fault tolerant control and data-driven method, and undergraduate capstone and Research Experiences for Undergraduates (REU) projects on cyber-resilience of autonomous vehicles, targeting towards underrepresented groups. This research will be grounded on nonlinear dynamical systems experiencing (i) proprioceptive sensor attacks, which target sensors that estimate the system's position, velocity, and other internal states, (ii) exteroceptive sensor attacks, which target sensors that gather information on the surrounding environment, and (iii) actuator faults. A unifying framework is planned to address (i)-(iii). In this framework, the system maintains a collection of safety filters, each of which constrains the control input at each time step in order to ensure safety under a particular failure or attack. Decision modules will also be developed for determining which safety filters are critical at each time step and which can be relaxed. Furthermore, exact conditions will be developed for formally verifying safety under multiple faults and attacks. The formal approach will build on foundations from algebraic geometry to formulate safety verification as a convex optimization problem. This framework will be compatible with physics-based and data-driven (neural network) system models under a variety of faults and attacks. The techniques will be validated through simulation and hardware evaluation on the PI's F1tenth racing testbed. 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

Program Summary Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by loss of motor neurons that leads to weakness, respiratory failure, and death within 3-5 years of symptom onset. The importance of prognostic and pharmacodynamic biomarkers in therapeutic development is highlighted by the emergence of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as potential neurodegenerative biomarkers for ALS. Neurofilaments (NFs) are represented by three subunits: NfL, neurofilament medium (NfM), and NfH that complex with -internexin in the central nervous system (CNS) or peripherin in the peripheral nervous system (PNS). NFs undergo extensive post-translational modifications (PTMs) (i.e. phosphorylation, O-glycosylation) that regulate neurofilament assembly, transport, and function and are known to form pathologic aggregates in ALS. An antisense oligonucleotide to SOD1, tofersen, was recently granted accelerated approval for hereditary SOD1-ALS based on its ability to lower NfL and pNfH by immunoassay in serum and CSF by ~60% at 12 weeks, long before clinical improvement was observed at one year. However, immunoassay methods are vulnerable to non-specific signals and are unable to discriminate between alternative isoforms or PTMs that may occur with disease. We have developed a proteomic assay for NfL that has indicated NfL exists only as truncated fragments in ALS CSF and have found that Coil 1 domain peptide species correlate best with ALS disease progression. We have also developed reagents and methods to extend analysis to NfM and NfH. By comparing neurofilament (NF) species in ALS and control biofluids, we anticipate that we will identify NF isoforms and PTMs unique to ALS. We will also measure NF isoforms pre- and post- tofersen treatment in blood and CSF from SOD1-ALS participants and compare their performance to existing NfL and pNfH immunoassays. We recently demonstrated that stable isotope labelling kinetics (SILK) can be safely employed in ALS participants and showed that mutant SOD1A5V protein turnover is faster than its wild-type counterpart. In this study, we will examine the effect of SOD1 lowering therapy on neuronal proteins, tau and NfL, and perform proteomic analysis to assess changes in protein expression pre- and post-treatment. We propose that in-depth proteomic and protein kinetic analysis of biofluids from the tofersen treated SOD1-ALS population provides an unparalleled opportunity to uncover biomarkers related to clinical improvement in ALS.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Post-traumatic joint contracture (PTJC) causes debilitating loss of motion following joint injury and is particularly impactful in the elbow. Clinical treatment is limited due to a poor understanding of key mechanisms leading to motion loss, making treatment targets elusive. This study will use a validated preclinical animal model of PTJC to identify the key aspects of physical- and biological-based interventional strategies that best limit PTJC following injury. Early joint remobilization improves range-of-motion (ROM); however, clinical practice requires a period of joint immobilization following injury to reduce instability and prevent joint overloading. The parameters of active therapy (i.e., initiation, duration, intensity) that best limit PTJC after an initial immobilization period without destabilizing or overloading the healing joint remain unknown. In addition, while studies have shown that modulation of the inflammatory response can improve healing after joint injury, and that T-cell-mediated signaling might represent a particularly effective target, protocols guiding inflammation-based therapeutic approaches for PTJC remain poorly defined. Overall objective: identify fundamental aspects of physical and biological treatment strategies (i.e., initiation, duration, intensity, synergy) that prevent the development of PTJC using a preclinical animal model and multi-modal, machine learning (ML)-based analyses. Aim 1: Identify parameters of voluntary active physical therapy that are most critical to minimizing PTJC while promoting healing after joint injury. This study will determine the optimal implementation of active physical therapy protocols to best preserve ROM yet limit load-induced damage. Image-based ML algorithms will be used to automate/accelerate spatial analysis of joint tissues and advance clustering analyses to elucidate cell- and tissue-level responses to physical treatments. Hypothesis: moderate intensity/duration physical therapy will maximize motion and limit joint damage, with additional benefit achieved by implementing a slightly staged increase in intensity after joint remobilization. Aim 2: Develop biological strategies to reduce PTJC using anti-inflammatory intervention and targeted modulation of the T cell mediated immune response following joint injury. Anti-inflammatory prevention strategies will be developed and strategically combined with physical therapy to target multiple phases of immune-mediated biological activity. ML algorithms will combine multi-modal experimental data to explore spatial relationships in PTJC pathophysiology. Hypotheses: (i) reducing inflammation in the post-injury and post-remobilization periods will help preserve ROM; (ii) improved outcomes from blocking T cell activity will demonstrate a key mechanism of PTJC etiology; (iii) ML-driven data analysis will determine that abrogation of capsule fibrosis, reduced remobilization-induced ligament hypertrophy, and limited T cell activity will be most predictive of preserved joint function. While results obtained using an animal model aren’t directly translatable to human care, this study will greatly advance understanding of PTJC pathophysiology and elucidate key principles of physical and biological interventional strategies that can be leveraged to inform future treatment of PTJC.

NSF Awards · FY 2024 · 2024-09

The CURB Engineering Research Center will transform U.S. manufacturing by valorizing waste CO2, empowering circular carbon economy, and creating quality biomanufacturing jobs. The U.S. energy and other industrial sectors emitted about 6 billion tons of CO2 annually, presenting a unique low-cost feedstock for the domestic supply chain. CURB will advance, deploy, and scale innovative hybrid electro-biomanufacturing engineered systems to empower a new circular carbon economy wherein CO2 will serve as valuable feedstock for manufacturing a broad range of products much more efficiently than current state-of-the-art and natural systems. CURB will create cost-effective and energy-efficient biomanufacturing technologies, facilitating the next-generation bioeconomy and empowering the domestic industrial supply chain for broad and essential chemicals, fuels, materials, and food. The emerging decarbonization and bioeconomy industries have grown rapidly to $4.5 and $4 trillion respectively, representing unparalleled opportunities for U.S. economic growth and millions of job opportunities. CURB uniquely converges these two sectors to turn our most daunting sustainability challenges into powerful catalysts for economic growth and prosperity in the U.S. Ultimately, CURB will transform U.S. manufacturing to zero- and negative emissions, valorize waste CO2 from broad industries, reduce hazardous compounds in emissions, build domestic supply chain with quality jobs, and produce plastics that are biodegradable rather than polluting. CURB will produce workforce pathways to success to empower rapid technology deployment and promote the competitiveness of domestic workforce. Through partners ranging from start-ups to major corporations, CURB’s technology commercialization will empower tens of billions of dollars in economic growth and promote national security as well as energy and manufacturing independence. In order to achieve these impacts, CURB will demonstrate the conversion of CO2 at a much higher conversion rate than the state-of-the-art using Hybrid Electro-Bio CO2 Utilization Systems (HEBCUS). The HEBCUS-engineered systems will use electrocatalysis to produce C2+ intermediates (e.g., ethanol, acetate, and propionate) that can enter primary metabolism with fewer steps than C1 intermediates and are compatible with many cell-based or cell-free biomanufacturing systems. The design will enable efficient conversion into a broad range of products at higher titer and productivity than platforms based on C1 intermediates. Soluble C2+ intermediates also substantially improve mass, energy, and electron transfers and overcome the gas-to-liquid transfer challenges of hydrogen and CO. CURB will focus on three interrelated research thrusts that converge scientific, economic, environmental, and social approaches with stakeholder needs for comprehensive system design and optimized societal impacts within three demonstration testbeds: CO2 conversion to (1) platform chemicals and polymer precursors, (2) biomaterials and biofertilizers, and (3) lipids and proteins. Convergent research will drive new transdisciplinary educational and training pathways for the biomanufacturing workforce of tomorrow, an estimated 10 million jobs. CURB will promote convergent research, broaden STEM participation from all Americans, and achieve broad societal impacts through engaging industries, communities, and the public. CURB’s Innovation Ecosystem, with many committed industry partners, will transform industries and communities, translate the CURB technologies, unleash economic growth potential, empower CURB sustainability beyond NSF funding, create and fill jobs with a competitive workforce, achieving multi-facet and tangible societal impacts. 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.