Northwestern University

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Patients diagnosed with breast cancer brain metastases (BM) have a poor prognosis, and their therapeutic options are minimal. Surgical intervention is limited to a single lesion, whereas most women present with multiple metastases, and most chemotherapeutic drugs are not effective due to the blood-brain barrier. Whole-brain radiation therapy is often the only available therapeutic option for patients with multiple and larger brain metastases. However, it is associated with potentially devastating side effects; therefore, there is an urgent need to develop new targeted therapies. Stem cell-based therapies have the potential to fulfill this need. The inherent tropism of neural stem cells (NSCs) towards solid and metastatic brain tumors after a local and systemic injection has been demonstrated by multiple studies. This specific property, along with the low immunogenicity of NSCs, has generated substantial interest in therapeutic applications using NSCs as carriers for targeted delivery of anti-tumor therapies in experimental animal models and translation to clinical trials for patients with glioblastoma. We have recently generated NSCs secreting therapeutic antibodies and tested NSCs' therapeutic properties in a BM model in pre-clinical studies. However, there has been no reliable methodology to monitor the intracranial behaviors of therapeutic NSCs in the complex in vivo brain environment. Therefore, it is imperative to devise non-invasive imaging modalities for tracking NSCs in the brain to ensure the quality of tailored development of NSC-based brain tumor therapies. Here, we propose to take advantage of a multimodal imaging approach combining an integrated single-photon emission microscope (SPEM) and magnetic resonance system that utilizes the inverted compound eye camera to track NSCs in the brain with high sensitivity and resolution. We hypothesize that this multimodal imaging platform will generate well-validated pre-clinical data necessary for successfully applying therapeutic NSCs to treat BM of breast cancer. The nanoparticle-based approach developed in our laboratory will be utilized for cell labeling with imaging agents. Three interrelated aims are designed to cover the scope of proposed studies. Specific Aim 1 will optimize SPEM/MR imaging for in vivo tracking of NSCs within the brain parenchyma. Specific Aim 2 will investigate the migration of NSCs within the brain of mice bearing BM using a multimodal imaging approach. Finally, Specific Aim 3 will investigate the influence of whole-brain irradiation on the distribution of NSCs within the brain of mice bearing BM. This system will provide an ultra-sensitive, non-invasive imaging platform for tracking NSCs in the pre-clinical model of BM of breast cancer and can be widely applied for imaging stem cell behavior in the context of other brain malignancies and solid tumors.

NIH Research Projects · FY 2024 · 2024-12

Project Summary/Abstract Inflammation and immune responses are critical in the body’s response to inflammatory injuries such as infection or tissue damage. Leukocytes, cells of the immune system, are recruited to these sites of damage or insult via a process known as the inflammatory cascade. In the inflammatory cascade, the step where leukocytes migrate out of the blood and across the endothelium is known as transendothelial migration (TEM) and occurs via interactions between leukocyte and endothelial PECAM and CD99. While much is known about the inflammatory cascade and subsequent neutrophil function in the systemic circulation and tissue beds, the process remains more elusive in the lungs. Understanding how types of leukocytes like neutrophils traffic from their sites of synthesis through the vasculature, migrate through the endothelium into the lungs and perform various functions (both pro-inflammatory and resolving) is of extreme importance due to the role of leukocytes in inflammatory pathology. When in the tissue, neutrophils perform many functions as granulocytic cells, resolving infection and insult, and are critical in ameliorating disease. However, they can also be damaging mediators of disease in their own right, contributing to inflammatory damage and disruption of normal physiological function. Two major forms of acute inflammatory airspace diseases in the lungs, gastric aspiration pneumonia and bacterial bronchopneumonia, have high prevalence and mortality and currently have no preventative therapies. The symptoms of these diseases in part are due to the crowding of the alveolar space, impaired gas exchange, and damage by neutrophils, and as such, high neutrophil presence correlates with adverse outcomes. However, neutrophils can also produce molecules known as specially pro-resolving mediators (SPMs) that are anti-inflammatory. Previous work shows that recruitment and migration of leukocytes in the lungs differs from the systemic circulation and neutrophil function is highly important in disease progression. I aim to interrogate the mechanisms by which neutrophils undergo TEM in the lungs during acute airspace disease and the functions they perform both individually and in concert with macrophages in the tissue and vasculature. I hypothesize that transmigration can be used to better pathology in infectious bronchopneumonia (Aim 1) and that there are populations of neutrophils that produce SPMs and interact with macrophages during lung injury (Aim 2). This will provide key mechanistic insights on TEM and function of neutrophils in the lungs, while also providing potential for therapeutic intervention and characterization of neutrophil roles in acute inflammatory airspace diseases.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT. Neurodegenerative diseases can have common, uncommon, and idiosyncratic manifestations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent and prolonged predilection for the anterior temporal lobe, a region critical for word comprehension on the left-sided hemisphere and non-verbal semantics (e.g., object recognition, contextualization of conduct) on the right. During the past 15 years, the Northwestern Primary Progressive Aphasia (PPA) Research Program has recruited one of the world’s largest cohorts of TDP-C cases. Each case has been deeply-phenotyped and longitudinally imaged and 25 have come to autopsy. In the course of these investigations, we have made important discoveries that have led to a theoretical overview of TDP-C, its distinctions from other forms of FTLD- TDP, its remarkable affinity for the anterior temporal lobe, and its impact on the fundamental process of language comprehension. These studies have raised new questions about TDP-C neuropathology. The current proposal aims to expand on these discoveries in ways that go beyond PPA by encompassing other clinical manifestations of TDP-C, their corresponding hemispheric asymmetry patterns, their distinctive impact on local cortical circuitry, and their relationship to the molecular fingerprints of the anterior temporal lobe. This proposal will benefit from synergies with the overall PPA program and the Northwestern ADRC and will, in turn, enrich both programs. The proposal revolves around three aims. Aim 1 will investigate the neuropathological concordance of TDP-C neuropathology with the asymmetric atrophy patterns seen in PPA versus other major neurobehavioral syndromes, each with a distinct pattern of asymmetric progression. Aim 2 will focus on the microcircuitry of these concordance patterns, namely the impact on inhibitory neurons and the laminar distribution of neurosynaptic perturbations. Aim 3 will address the transcriptomic patterns that potentially earmark the anterior temporal lobe for special vulnerability to TDP-C in each syndrome, each with different asymmetries of vulnerability. Although TDP-C is a relatively rare disease it offers unprecedented opportunities for understanding the general biologic mechanisms of selective vulnerability in neurodegenerative disease. An additional consequential outcome would be to discover druggable protein targets that interfere with the destructive effect of TDP-C on the anterior temporal lobes.

NIH Research Projects · FY 2026 · 2024-12

Project Summary The mammalian cochlea contains two types of specialized mechanosensors, inner and outer hair cells (IHCs and OHCs), surrounded by distinct inner and outer supporting cell types and differentially innervated by afferent and efferent neurons. The resulting structure and neuronal circuitry are critical for hearing. Our eventual goal is to elucidate how this neural circuit assembles during development, and our overall approach is to alter the identity of some of the cell types involved. In this proposal, by removing or adding the master regulator TBX2 at various times in development we will generate mice with no IHCs and mice in which IHCs convert into ic-OHCs (inner compartment outer hair cells, in the position of the IHCs but with most of the features of OHCs and not of IHCs) at the time of our choosing, either permanently or reversibly. With these manipulations we will be able to address many unanswered questions regarding how auditory neural circuits assemble, such as which cells direct type I afferents to IHCs and their vicinity, what normally limits type II afferents to innervate only OHCs, what is the role of afferents in dictating how and where efferents terminate, and what is the role of IHCs, their contact with type I afferents, and their synaptic communication with them in the formation and maturation of the distinct subtypes of cochlear afferents. Finally, we hope to elucidate whether the contact and formation of functional synapses between IHCs and type I afferent neurons of the cochlear spiral ganglion is restricted to critical developmental periods or may occur later in life.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Psychomotor disturbance is a core feature of depression which, despite longstanding recognition and evidence that it may be predictive of clinical course, is not well-studied. Electroencephalogram (EEG) is an inexpensive and easily implemented method for recording neural activity and increased resting-state EEG coherence in the beta band (13-30 Hz) has been linked with motor dysfunction (e.g., in Parkinson’s, normal aging). Similarities in Parkinson’s and depression such as hypodopaminergic activity in the basal ganglia and altered functional connectivity of motor-related brain regions suggests that shared mechanisms may underlie motor dysfunction in both populations; however, no research has examined the connection between psychomotor disturbance and resting state EEG coherence in the beta band. Additionally, assessment of psychomotor disturbance has often relied on self-report measures or behavioral coding performed by trained raters which may both be subject to bias (e.g., a rater who knows an individual has been diagnosed with depression may be more likely to indicate presence of psychomotor disturbances). The identification of a biomarker could eliminate this concern in assessment and inform improved development of treatment for depression and individualized treatment recommendations. The current proposal will address these questions using a longitudinal investigation of neural abnormalities in currently depressed, remitted depressed, and never depressed individuals (Aim 1). Resting-state EEG coherence in the beta band will be compared to state-of-the-art instrumental measurements of psychomotor disturbance (Aim 2) to validate this marker of motor dysfunction which has been recorded in other populations (e.g., Parkinson’s) against psychomotor disturbance. To determine the predictive utility of EEG coherence as a biomarker for course of illness in depression, associations between the neural measures from Aim 1 and symptom severity, functioning, and quality of life 6 months later will be examined (Aim 3). Training Plan: An extensive training plan has been developed to enable the Applicant to effectively complete the project. Through coursework, colloquia/conference attendance, workshops, and weekly meetings with the sponsors, the Applicant will develop theoretical expertise in motor pathology in depression, as well as specialized skills in the EEG coherence technique and longitudinal research design and statistical analysis. This training plan was designed to facilitate the Applicant’s career aspirations as a research scientist with the sound theoretical foundation and methodological expertise necessary to conduct her own independent program of research. Training Environment: The project will take place at Northwestern University, an ideal training environment given the accessibility to cutting-edge resources, equipment, and coursework at the site. Further, both the Sponsor and Co-Sponsor are located at the institution and are experts in the theory and methods needed to meet the Applicant’s training aims.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ABSTRACT A critical yet still poorly understood step in HIV-1 infection is the early post-entry trafficking of viral cores across the cytoplasm to reach the nucleus. This requires directed and controlled transport along microtubule filaments by host motor complexes, but precisely how viral cores control these processes is only beginning to be defined. This is in part due to the unusual structure of the HIV-1 core, which is a metastable fullerene cone composed of ∼250 hexamers and 12 pentamers of capsid protein (CA), and its equally unusual and enigmatic strategies for engaging microtubule motors. Our lab was the first to demonstrate that incoming HIV-1 particles induce the formation of specialized stable microtubule subsets to facilitate their long-range transport to the nucleus. We subsequently discovered the first HIV-1-associated cellular motor adaptor, Fasiculation and Elongation Factor Zeta 1 (FEZ1). Binding to FEZ1 enables viral recruitment and control over the outward- directed motor, kinesin-1, which often exhibits higher affinities for stable microtubules. Using a variety of genetic and biochemical approaches combined with live cell imaging of infection in biologically relevant cell types, our data further revealed that localized phosphorylation of FEZ1 on viral cores allows HIV-1 to regulate kinesin-1 activity. This in turn controls the bi-directional movement of virus particles, a key process that allows cargos to navigate the densely crowded cytosol while ultimately favoring net forward displacement to reach the nucleus. While FEZ1 phosphorylation enables viral control over Kinesin-1, our data now demonstrates that distinct coiled coil (CC) domains in FEZ1 mediate its binding to viral capsids through high avidity charge-based recognition of hexamer pores, yet the exact structural basis of these interactions and their functional roles in infection remain unknown. Preliminary data further shows that each of FEZ1’s four CC domains play a role in infection. Based on structure modeling using AlphaFold3, we hypothesize that CC2 and CC4 mediate binding to capsids while CC1 and CC3 regulate kinesin-1 engagement. Additional preliminary data further reveals that FEZ2 is a structurally and functionally divergent paralog of FEZ1. Structural comparisons suggest that FEZ2 contains distinct CC domain organizations that still mediate interactions with HIV-1 capsids but lacks kinesin- regulatory domains. In line with this, we find that FEZ2 inhibits HIV-1 trafficking to the nucleus and the establishment of infection. Furthermore, our data demonstrate that FEZ2 is differentially expressed relative to FEZ1 in different biologically relevant cell types. From these data, we hypothesize that divergence in their CC domains underlies the distinct pro- and anti-viral activities of FEZ1 and FEZ2 proteins, respectively, and their relative expression levels serve as an important determinant of cellular susceptibility to infection. Developing a detailed structural and functional understanding of how FEZ family members interplay and exert opposing effects on infection will not only provide fundamental insights into poorly understood aspects of HIV-1 infection but may also guide the future development of targeted antivirals that disrupt these capsid-based interactions.

NIH Research Projects · FY 2026 · 2024-11

Summary Effective treatment of chronic viral infections, a critical global health issue, relies on understanding the signaling and metabolic pathways involved in overcoming CD8 T cell exhaustion. In both acute and chronic LCMV infection, there is a metabolic switch from catabolism to PI3K-AKT-mTOR driven anabolism when naïve CD8 T cells undergo activation, expansion, and differentiation in the early phase. While CD8 T cells shift from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) during acute infection, along with the resolution of the virus and the transition from effector to memory cells, continuous antigenic stimulation during chronic infection leads to a state of dysfunction called "exhaustion," characterized by metabolic insufficiency and dysfunctional mitochondria. Recent research from the investigator’s team and others has shown that the previously recognized "exhausted" CD8 T cells are diverse and can be divided into at least three main subsets. Among them, TCF-1hi progenitor (TPRO) cells act as self-renewing precursors that give rise to more terminally differentiated PD-1hi exhausted (TEXH) cells or CX3CR1hi effector (TEFF) cells. Computational analysis from the team has revealed that TEFF cells are more metabolically active than exhausted cells, operating under a distinct metabolic program to meet the demands of long-lasting antiviral effector function. Additionally, they have identified that the CX3CR1hi TEFF CD8 T cell subset is formed in a CD4 T cell-derived IL-21-dependent manner, exhibits potent cytolytic function, and plays a crucial role in viral control during the late phase of chronic infection. In contrast to IL-2, which rapidly declines during the early phase of infection, IL-21 is consistently produced by CD4 helper T cells throughout the chronic phase of LCMV Cl13 infection. The team has further shown that IL-21 does not strongly activate PI3K-AKT-mTOR pathway. Instead, IL-21 signals through JAK-STAT and induces the expression of Pim1. Interestingly, Pim1, a member of the Pim kinase family, is considered an emergency backup for the PI3K- AKT-mTOR pathway due to shared downstream targets such as S6 kinase, 4E-BP, and Bad. Consequently, Pim1 has been regarded as being dispensable for T cell activation, expansion, and function, as evident from the lack of significant differences in effector and memory differentiation during acute LCMV infection. However, the preliminary data from the team indicate a significant reduction in CX3CR1hi TEFF cells in Pim1 knockout mice following chronic LCMV Cl13 infection. This suggests that while Pim1-mediated cellular metabolism is dispensable in the early phase of infection when IL-2 signaling and PI3K-AKT-mTOR pathway dominate, it becomes particularly important and necessary when late TEFF cells arise from the progenitor subset driven by CD4 T cell-derived IL-21. Based on these findings, they hypothesize that the IL-21-Pim1 signaling axis regulates the metabolic adaptation of late TEFF cells, supporting their differentiation and function during the chronic phase of viral infection. To test this hypothesis, they will examine the importance of the IL-21-Pim kinase pathway and the associated molecular mechanisms that govern the cellular metabolism of TEFF cells in the proposed studies.

NIH Research Projects · FY 2026 · 2024-11

Summary/Abstract Germinal Centers (GCs) are specialized anatomical sites in the secondary lymphoid tissues where high-quality adaptive immune responses are mounted. B cells within GCs undergo intricate transcriptional and epigenetic transitions to ultimately generate effective humoral immune responses. During the GC B cell responses, specific transcription factors define distinct stages of cellular differentiation, and efficient chromatin remodeling ensures systematic transition between these transcriptional programs. Brg1/Brm-associated factor (BAF) complexes are highly conserved nucleosomal remodelers that play pivotal roles in establishing cell-specific gene expression programs during cellular differentiation and development. Notably, BAF subunits ARID1A, ARID1B, and SMARCA4, are each mutated in ~10% of Diffuse Large B-Cell Lymphoma (DLBCL) originating from GCs, underscoring the regulatory functions of BAF complex activity in maintaining GC homeostasis. However, the specific contributions of distinct BAF complexes in GC biology remains unclear. Our recent studies showed that the AT-rich interacting domain 1 (Arid1a) dependent canonical BAF complex (Arid1a-cBAF), is indispensable for GC responses, and therefore, generation of high-affinity antibodies. Arid1a- deficient B cells can initiate the GC program but fail to sustain GC responses. We identified important roles of Arid1a-cBAF for establishing permissive chromatin landscapes during B cell differentiation, and simultaneously suppressing inflammatory gene programs to maintain transcriptional fidelity in GCs. Moreover, inflammatory signatures emanating from Arid1a-deficient B cells led to enhanced neutrophil and monocyte recruitment and anti-inflammatory glucocorticoids rescued the differentiation of Arid1a-deficient GCs. These studies suggest that Arid1a-cBAF activity restricts inflammatory signals through both cell-intrinsic and -extrinsic mechanisms to preserve GC responses. We hypothesize that Arid1a-dependent BAF activity establishes the GC transcriptional program and simultaneously restricts inflammatory signatures to promote efficient GC B cell responses. To address this hypothesis in this proposal we will: i) elucidate the epigenetic control of GC B cell differentiation by Arid1a-cBAF activity (Aim1) ii) examine the roles of inflammatory signatures associated with Arid1a loss in disrupting GC responses (Aim2) iii) define altered immunological landscapes and dissect their contributions to perturbation of GCs upon Arid1a loss (Aim3). In summary, the proposed studies will provide comprehensive mechanistic insights for the role of cBAF-mediated nucleosomal remodeling in establishing robust GC responses. These efforts will enhance our broader understanding of inflammation and immunity. In addition, our work will add to an emerging paradigm describing a paradoxical role of unrestrained inflammation in limiting GC responses, commonly seen in patients with severe pathogen infections and sepsis.

NIH Research Projects · FY 2024 · 2024-11

Summary/Abstract The hippocampal mossy fiber (MF) synapse exhibits robust short term presynaptic plasticity that is responsible for gating the flow of information into the CA3 region. MF axons make synapses with both CA3 pyramidal cells (PCs) and stratum lucidum interneurons (SLINs), producing both direct excitation and feedforward inhibition onto the local network. The properties of these synaptic connections have divergent phenotypes with MF-PC synapses showing facilitation and the MF-SLIN synapse depressing during a burst of granule cell activity. This results in a net effect of reduced inhibition and increased excitation during bursts of high frequency presynaptic firing that causes suprathreshold activation of CA3 PCs. Despite a large body of research on these synaptic mechanisms, it is not clear what underlies this divergent synaptic behavior of synapses formed by the same axon and in some cases by different compartments of the same presynaptic terminal. The goal of this fellowship is to determine if the high affinity Ca2+ sensor synaptotagmin 7 (Syt7), is responsible for creating this high pass filter in the area CA3. To address this question I will utilize a newly created conditional knockout mouse line where Syt7 is lost in MF presynaptic terminals. I will determine if Syt7 demonstrates compartmentalized activity at MF to PC and MF to SLIN connections, and thus constitutes the molecular mechanism for this circuit's behavior. Using genetic replacement approaches I will determine whether the C2 Ca2+ binding domains are necessary to explain the function of Syt7 in MF synapses. Furthermore, using high resolution biochemical and microscopy approaches I will determine the subcellular location of Syt7 in MF synapses to understand how the protein’s localization informs its function. Identifying the presynaptic mechanisms responsible for information transfer will allow future work to directly test the molecular processes underlying complex hippocampal-dependent behaviors.

NIH Research Projects · FY 2024 · 2024-11

Project Summary/Abstract Theories about the origin of perceptual abnormalities (attenuated hallucinations) have been evoked for centuries. One competitive theory is that perceptual abnormalities can be explained by atypical predictive coding. The predictive coding theory states that individuals use prior knowledge to create a mental model of the environment and that mismatches of expectancy and experience lead to an updating of the prior mental model. In people on the psychosis spectrum, more weight is given to the prior models and belief updating does not occur. According to this theory, people who experience perceptual abnormalities misattribute the prior expectation as a sensation leading to a perceptual experience. Adjacently, recent research in non-psychiatric populations has investigated the mechanisms of mental imagery. When imagined signals are strong enough, they can become subjectively indistinguishable from reality. Taking this novel research into account, it may be possible that the vividness of mental imagery may affect the strength of prior beliefs and make it more or less likely to experience perceptual abnormalities. Thus far, the role of mental imagery in the predictive coding theory of perceptual abnormalities has not been explored. The proposed study will examine the role of mental imagery in predictive coding using samples of people at clinical high-risk for psychosis (CHR) who experience perceptual abnormalities (N = 40), CHR individuals who do not experience perceptual abnormalities (N = 40), and healthy controls (N = 40). Participants will partake in a clinical and cognitive assessment, including two novel mental imagery tasks that instruct participants to imagine a sound or image and test their ability to differentiate between imagined and real stimuli later in the task. Additionally, participants will complete a self- report questionnaire about their mental imagery and perform a predictive coding task. Using this data, the study will investigate three aims to understand whether the vividness of mental imagery relates to the presence of perceptual abnormalities and if this improves the predictive coding model. Aim 1: validate the mental imagery task and mechanisms in the CHR population. Aim 2: assess whether the vividness of mental imagery relates to the severity of perceptual abnormalities. Aim 3: examine whether mental imagery can be incorporated into the predictive coding model. Training Plan: to complete this project and build an independent research career the applicant will (a) develop an understanding of theories and mechanisms of hallucination formation, (b) gain comprehensive experience with building and interpreting computational models, and (c) learn the principles and applications of structural equation modeling. This training will be accomplished through regular meetings with a team of expert scholars, coursework, workshops, and attending conferences. Training Environment: The training will take place at Northwestern University, which offers an excellent and collaborative training environment. The environment, alongside the proposed study and training plan, will position the applicant to launch a career researching the influence of cognition on positive symptoms.

NIH Research Projects · FY 2024 · 2024-10

PROJECT SUMMARY Purinergic signaling plays fundamental roles in activities of the nervous system as diverse as neuroprotection, synaptic transmission, nociception, inflammation, hearing, and taste. This process is initiated by releasing adenosine triphosphate (ATP) across the membrane through either classic exocytosis or ATP-permeable channels into the synaptic cleft, where the ATP binds downstream receptors on an adjacent cell. There are five families of ATP release channels: connexins, pannexins, volume-regulated anion channels, maxi channels, and calcium homeostasis modulators (CALHMs). Highly expressed in the brain and taste buds, CALHM channels play essential roles in taste and neuron transmission, and their dysregulation has been associated with various neurological disorders including Alzheimer disease, ischemic brain damage, and depression, making CALHM channels important pharmacological targets. The CALHM family consists of three members, CALHM1, 2, and 3. They are voltage-dependent, extracellular, calcium-concentration-regulated, nonselective ion channels that are permeable to the signaling molecules ATP and calcium. They are predicted to share membrane topology with connexins, pennexins, innexins and VRACs. Functional studies provide a consensus view that CALHM1 forms a hexameric channel and that it forms only hemichannels, but not gap junctions. CALHMs activity is modulated by a wide range of factors including ruthenium red, Gd3+, and 2-APB. Although CALHMs are central to human physiology and are potential therapeutic targets, there are no structures of this family. We do not understand, in molecular detail, how the channel is activated or inhibited, or how it is modulated by small molecules binding at specific sites. We have published strong evidence that CALHM2 is undecameric and exists as both hemichannels and gap junctions in vitro. We have determined cryo-EM structures of human CALHM2 in the Ca2+-free open state, and ruthenium red–bound inhibited state. These preliminary results provide not only the first atomic structures of a CALHM family member, but also the first bona fide structure in an inhibited state, which has never been reported for channels with similar topology including connexins, pannexins, innexins and VRACs. We observed a binding site of ruthenium red that was completely unknown before. Building on this preliminary data, we propose to continue the structural studies of CALHM2 and the other two family members, CALHM1 and CALHM3, combined with complementary electrophysiology experiments and other functional approaches, to define the molecular basis for a comprehensive gating mechanism and the molecular determinants and function of gap junction formation, as well as their pharmacology. These advances will provide a solid foundation for developing new drugs against neurodegenerative diseases and for a deeper understanding of the function of the ATP release channel family and the gap junction family.

NSF Awards · FY 2024 · 2024-10

With the support of the Chemical Structure and Dynamics (CSD) Program in the Division of Chemistry of the National Science Foundation (NSF) and the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG) Lead Agency Activity in Measurements of Interfacial Systems at Scale with In-situ and Operando Analysis, Professor Franz Geiger of Northwestern University and Professors Braunschweig and Ravoo of the University of Muenster are studying molecular aspects of photoswitchable surfaces comprised of self-assembled monolayers of arylazopyrazole (AAP) derivatives.The wetting of solid surfaces by liquids is known from everyday experience and is surprisingly easy to observe - just consider a bathroom mirror fogging and clearing up with changing relative humidity. Yet, changing the surface properties of a material with spatially and temporally directed external stimuli such as relative humidity, light, or applied potential in a controlled and reversible way is a formidable challenge. This project addresses this challenge by quantifying, under operando conditions, key molecular and structural properties of the "on" and "off" states of a molecular switch. Their studies could contribute to the fundamental understanding that is needed to predict and control the wettability of surfaces for applications in microfluidics and green energy technologies. The project will offer opportunities for graduate student training in an international, cross-Atlantic research environment and interdisciplinary training across organic synthesis, nanotechnology, thin film measurements, and advanced nonlinear optical spectroscopy. Trainees will participate in 2 month-long laboratory exchanges each year and participate in outreach opportunities through science blogging and high school outreach in Germany and the U.S. The team will use a unique combination of surface-specific spectroscopies (vibrational sum frequency generation and electronic second harmonic generation) to study the mechanism of AAP isomerization and the resulting changes in wetting properties of the surface. Self assembled monolayers (SAMs) of AAP derivatives will be studied in contact with electrolyte solutions as well as humid air. Changes in surface group orientations will be correlated with applied voltages and solvent exposure to gain molecular insights into the role of water dynamics on reactions at the interface. Patterning of the SAMs by microcontact printing will allow for the study of edges and defects Iin their structural order. While focus is placed on fundamental studies of switchable surfaces, this research will also provide new insights into the dynamics of solvents at electrodes surfaces, the structure of Stern layers, and the distribution of surface potentials in operando. 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 · 2024-10

Environmental accumulation of postconsumer plastics, including poly (ethylene terephthalate) (PET), is a significant ecological concern. Various chemical recycling technologies are being actively developed to address plastic waste management issues and their threat to the environment. Methods that use chemical solutions can facilitate the recovery of building blocks called monomers. These building blocks can be used to synthesize new-like PET or generate other materials and chemicals. However, moving the target products through in the solutions can be challenging, especially at temperatures below the melting point of PET. At these temperatures the solutions can become thick and or the feedstock is less soluble in most conventional solvents. Therefore, this research program will investigate how CO2-H2O mixtures can be used as a tunable media to reduce these challenges and better break-down PET into its monomeric compounds for recycling/ upcycling. The research will be conducted by a team of researchers located at the University of Kansas and Northwestern University in collaboration with researchers at Washington University in St. Louis and SLAC National Accelerator Laboratory. The technical and environmental impacts of this project are significant, given the millions of tons of waste plastics that must be recycled or chemically transformed into valuable products. The researchers will receive cross-disciplinary training in science and engineering, attend communication workshops and conduct outreach activities, and work collaboratively in partnering universities and National laboratories. This project is built around the high-media tunability offered by near-supercritical and supercritical CO2 (scCO2) to minimize the limitations of chemical recycling processes. The limitations encompass poor accessibility of catalysts and reagents in a viscous semi-crystalline polymer matrix and thermodynamic barriers pertaining to polymer morphology and structure. These impact the reactivity and selectivity during solvent-based deconstruction of waste plastics. The two primary aims of this project are (1) to elucidate the impact of CO2 on PET polymer morphology, phase behavior, and reagent transport during acid-catalyzed hydrolysis, and (2) to understand the deconstruction of semi-crystalline PET in CO2-tunable media mechanistically. Advanced ex situ and in situ/ operando analytical techniques, such as small- and wide-angle X-ray scattering (SAXS/WAXS) and Magic Angle Spinning-Nuclear Magnetic Resonance (MAS-NMR) Spectroscopy will be leveraged to generate fundamental knowledge on how CO2 impacts polymer phase behavior, morphological and thermal properties as well as solvent transport at varying temperatures and pressures. A detailed kinetic Monte Carlo model will be developed to provide insights into the reaction and transport mechanisms of hydrolytic deconstruction of PET into monomers in the presence of CO2. This work will also put forward a state-of-the-art methodology blueprint, which can be adapted to expand multi-scale mechanistic studies to other chemical recycling strategies for post-consumer plastics. 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 · 2024-10

The NSF-Simons AI Institute for the Sky (the SkAI Institute) will draw together top researchers across the country to unleash the discovery potential of revolutionary sky surveys and solve fundamental problems at the forefront of astrophysics and artificial intelligence (AI), transforming our understanding of stars, galaxy formation and evolution, and cosmology and the early Universe. Fulfilling this promise requires overcoming enormous challenges in analysis and inference from enormous, heterogeneous, multi-modal datasets, developing physically accurate simulations, and designing ever more complex astronomical instruments and surveys. SkAI astrophysicists, foundational AI researchers, educators, AI ethicists, software engineers, and artists will work together to accomplish SkAI’s research goals and develop effective and transferable programs to grow a large and diverse Astro-AI and STEM workforce. SkAI will unite 25 partner organizations to form an inclusive, cross-disciplinary nexus centrally located in Chicago and the Midwest, with research and education bridges to Georgia, Hawaii, and Alaska, seeding and nurturing a diverse generation of interdisciplinary leaders in science and engineering. SkAI will leverage the fast-paced revolution in AI and the data revolution in astrophysics to revolutionize both fields. SkAI researchers will tackle some of the grandest open questions in astrophysics, spanning 20 orders of magnitude in scales of time and space, probing the nature of stars, compact objects, and transients, galaxy formation and evolution, and the cosmic history of our Universe. The institute will achieve foundational AI breakthroughs in generative models, necessary for scaling to large, heterogeneous datasets and for combining simulations with data-based approaches to modeling; astrophysics-informed and interpretable architectures, needed to infer physically meaningful parameters and gain new insight into the information latent in large datasets; and uncertainty quantification, to guarantee reliable scientific results and conclusions. The SkAI team will integrate Astro-AI efforts and resources around three pillars that mirror the scientific-process elements of data, simulations, and experiments: enhanced inference from cosmic survey data, AI-accelerated simulations with multi-scale astrophysics, and learning-based astrophysical survey and instrument design. Through interactive workshops, summer schools, a vigorous visitors program at the SkAI Hub in Chicago, and the release of ethical and easy-to-use community software, SkAI will engender a broad collaborative basis for interdisciplinary science involving a diverse and inclusive group of AI researchers, astrophysicists, engineers, and students. This institute is jointly funded by the NSF and The Simons Foundation. 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 · 2024-10

Non-technical description: Structural proteins enable spectacular mechanical feats in biology, including the persistent attachment of mussels to all underwater surfaces or the ability of the locusts to jump many times their height. At the core of this performance is the sequence of amino acids, each of which has evolved over billions of years to achieve its desired function. However, it is still impossible to predict and engineer the function of proteins directly from their amino acid sequence. This research imitates the natural evolutionary processes to develop robust biomaterials and adapts them to (1) develop biomaterials with unprecedented performance and (2) discover how key aspects of their amino acid sequences lead to this performance. The proposed “directed evolution” approach combines techniques in synthetic biology with novel methods for measuring the mechanical properties of thousands of samples. In the proposed data-driven approach, these experimental results over large datasets are iteratively informed by simulations and machine-learning algorithms. Technical description: This DMREF project aims to design protein-based biomaterials including (1) Mussel foot proteins (Mfps) with superior underwater adhesion over wildtype sequences, and (2) Resilin-inspired bioelastomers with high strength while retaining the mechanical resilience found in nature. The proposed directed evolution concept is to pair the expression and purification of large libraries of mutant genes with new high-throughput characterization techniques for mechanical properties. The proposed approach enables the selection of the best performers over thousands of mutants, which can then be subjected to subsequent evolutionary cycles. Successful implementation of the proposed methodology aims to advance predictive modeling, design, synthesis, and testing of next-generation structural biopolymers enabled by synthetic biology. This proposal also aims to train undergraduate and graduate students in a Materials Genome Initiative (MGI) context, while expanding educational outreach activities associated with biomaterials design. Data generated are proposed to be shared to the community through servers developed as part of MGI. 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 ABSTRACT This project will rigorously assess the impact of recreational cannabis legalization on opioid use and overdoses across the United States. With nearly half of the U.S. population living in states where recreational cannabis is legal, and ongoing policy shifts influencing its availability, this research is both timely and critical. The study will have two specific aims: first, to measure the effects of recreational cannabis legalization on substance use for self-management of pain, utilizing a nationally representative survey with detailed drug-use data; second, the project will quantify the impact of these policies on opioid morbidity and mortality, combining survey data with nationwide overdose data to assess changes in non-fatal and fatal overdoses. For each aim, the team will test for differences in the impact of cannabis legalization across 1) policy implementation characteristics and 2) individual sociodemographic determinants of health. The research approach will employ a rigorous, quasi- experimental statistical methodology, led by a multidisciplinary team of experts in substance use policy research, addiction medicine, and statistical methods. The outcome of this study will provide crucial evidence- based information to inform policymakers and public health officials in crafting effective interventions that address the complex relationship between cannabis policy, health disparities, and substance use outcomes.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Antibiotic overuse is a serious public health crisis. Antibiotics are one of the most commonly prescribed medications where 7 of every 10 Americans receive an antibiotic annually. This is concerning considering that it is estimated that ~30% of antibiotics prescribed in outpatient clinics are unnecessary. Whether appropriate or inappropriate, antibiotic use can result in adverse events including allergic reactions, Clostridioides difficile infection (CDI), and antibiotic resistance. Antibiotic stewardship (AS) is recommended to optimize antibiotic use and curb inappropriate antibiotic prescribing and encompasses strategies such as academic detailing, audit and feedback, and laboratory testing. AS strategies have been shown to improve prescribing, while decreasing costs, antibiotic resistance, and CDI. We have recently begun quality improvement activities to support the implementation of AS strategies described in the CDC Core Elements of Outpatient Antibiotic Stewardship in urgent care clinics and Federally Qualified Health Centers (FQHCs), which generally serve underserved and vulnerable patient populations in the Chicagoland area. A new accreditation standard was recently published by The Joint Commission (TJC) recommending that a focus on health equity and disparities be integrated within existing quality improvement activities like the Core Elements. This is significant because disparities in antibiotic prescribing have been identified, where Black patients are less likely to receive antibiotics than White patients, but more likely to receive inappropriate prescribing. In addition, several individual and provider characteristics have been found to be associated with unnecessary prescribing but are limited as these studies do not interrogate the drivers of these disparities such as structural determinants or the patient experience. Evaluating implementation of AS strategies through the lens of structural inequities and the intersection with other patient and provider characteristics are critical for informing and enhancing uptake of AS strategies and their impact on patient outcomes. We propose to conduct a mixed methods study using surveys to evaluate facility implementation of AS and equity standards; electronic health record (EHR) data from urgent care and FQHC clinics to evaluate disparities in antibiotic prescribing; and qualitative interviews with patients to interrogate the factors that shape variation in antibiotic prescribing and equity in prescribing. The expected outcomes of this study are to close the knowledge gap on understanding drivers of inequity and identify strategies to facilitate equitable antibiotic prescribing in resource-limited settings that treat vulnerable patients, such as FQHCs. This project is significant and innovative because using a mixed methodology to incorporate health equity evaluation with AS implementation represents a significant paradigm shift and has not been rigorously evaluated. Evaluating implementation of AS strategies and equity standards and their relationship with disparities in antibiotic prescribing (whether minimizing or exacerbating) will have impact by informing interventions to improve and ensure equitable antibiotic prescribing and reduce unnecessary antibiotic prescribing.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Nicotinamide adenine dinucleotide (NAD+) and its reduced form NADH, play crucial roles in maintaining tissue homeostasis. We now know that NAD+ and NADH concentrations differ in different parts of the cell by orders of magnitude. Nevertheless, how these distinct cellular pools of NAD+/NADH enable compartment specific metabolic and regulatory functions, ensuring coordination of various cellular processes remains elusive. NAD+/NADH compartmentalization is particularly important for the kidneys, in which tubule cells perform the high-energy demanding task of reclaiming solutes filtered from the bloodstream and eliminating waste products through urine. In acute kidney injury (AKI), a common condition in elderly patients, substantial decreases in the levels of NAD+ impair energy generation in tubular epithelial cells leading to critical loss of cellular and organismal homeostasis. Patients who survive AKI frequently develop chronic kidney disease (CKD), a condition characterized by kidney fibrosis and inflammation leading to deleterious systemic effects. We and others have shown that NAD+ boosting by cytoprotective approaches protects the kidney tubules against ischemia and other insults. Furthermore, several experimental studies have demonstrated protective role for NAD+ precursor supplementation against aging and AKI but the underlying mechanisms remain elusive. In particular, while the cellular NAD+/NADH ratio is critical for energy metabolism, the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. To successfully translate NAD-based therapeutics in humans, it is essential to understand the molecular mechanisms by which this metabolite regulates kidney health. To this end, recent technological advances that allow genetic manipulation of NAD+ in different cellular compartments, have uncovered an exciting potential for revealing the multi-faceted effects of this fascinating molecule. The goal of this proposal is to identify novel mechanisms by which directly increasing the NAD+/NADH promotes kidney health in the context of injury and aging. To this end, we propose in vivo expression of Lactobacillus brevis (Lb)NOX, a bacterial water forming NADH oxidase, in the cytosol or mitochondrial of kidney tubular cells. Two specific aims are proposed. Aim 1 will determine how boosting mitochondrial NAD+/NADH ratio in tubular epithelial cells regulates kidney health following ischemic kidney injury. Aim 2 will define the role of boosting cytosolic NAD+/NADH in tubular epithelial cells as a regulator of kidney health following ischemic kidney injury. Completion of this project will generate exciting new insights in kidney biology and enable the development of urgently needed novel therapeutics that protect kidney health.

NIH Research Projects · FY 2025 · 2024-09

Abstract Neisseria gonorrhoeae is an obligate human pathogenic species. A few reports in the literature describe three or four genomic islands encoding potential double-stranded phage genomes, and only one manuscript reports the production of a double-stranded phage. However, there are issues with the rigor of that report. We have also published that sublethal hydrogen peroxide treatment induces the expression of some genes carried in these phage islands (Quillin, et al.-2018). Moreover, two saturating transposon screens failed to isolate transposon insertions in some phage island genes (Hu, et al.-2020, Remmele, et al.-2014). We have developed a CRISPR interference (CRISPRi) system for N. gonorrhoeae (Geslewitz, et al.-2024) and have used it to show that repression of two of the three phage-island encoded LexA orthologs is lethal. Down- regulation of one ortholog by CRISPRi results in the production of phage particles as assayed by transmission electron microscopy. We will determine whether one or more phage islands can produce phage, explore whether the two essential LexA orthologs are regulated similarly to the canonical LexA, and determine whether these phage(s) can infect Neisseria strains or species.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Impaired pragmatic (i.e., social) language is a defining symptom domain of autism spectrum disorder (ASD) and imposes significant burden on affected individuals and their families throughout the lifespan. A wealth of evidence demonstrates that pragmatic abilities are highly heritable and are a primary feature of the broad autism phenotype (BAP) seen in unaffected relatives of autistic individuals. Further, pragmatic language differences that mirror those in ASD and the BAP are observed in carriers of FMR1 mutation conditions (e.g., fragile X syndrome and the FMR1 premutation), implicating this high confidence ASD risk gene in the ASD pragmatic phenotype. In addition to being valuable targets for intervention, pragmatic language abilities also appear to be sensitive to genetic liability to ASD, and so can provide a window into the biological origins of ASD symptomology. Extensive evidence from our prior work and current NIMH-funded R01 (R01MH091131) has reported overlapping profiles of impaired pragmatic language and related molecular-genetic and neurobiological correlates in ASD and in FMR1 mutation carriers. In this project, we advance this work by investigating the mechanistic origins of these differences, with a focus on motor-speech abilities shown to be disrupted in ASD and the BAP which are related to pragmatic language skills, in carriers of the FMR1 premutation (PM), to illuminate gene-brain-behavior pathways associated with this core ASD symptom domain. Preliminary data show robust differences in motor- speech skills among PM carriers that are qualitatively similar to those observed in ASD and the BAP, and which relate to high-order pragmatic-related abilities and neurobiological and molecular-genetic variation. Specifically, Aim 1 characterizes the motor-speech skills that contribute to ASD-related pragmatic profiles in PM carriers through a targeted battery of assessments indexing mechanistic contributors to pragmatic language including speech articulation, audio-motor synchronization, rhythmic speech fluency, and auditory feedback control. Aim 2 examines associations between targeted motor-speech skills and profiles of core, high-order pragmatic abilities in PM carriers. Finally, Aim 3 investigates both neural and molecular-genetic influences on motor-speech skills and their relationship to broader ASD-related pragmatic profiles in PM carriers. Together, these aims will inform the complex relationships between neurobiological and genetic markers, motor-speech mechanisms, and ASD- associated pragmatic abilities that may be linked with FMR1-related variation. This theoretically driven, targeted, and efficient study design will leverage rich and extensive existing data to uniquely reveal mechanistic and biological origins of this significant ASD clinical symptom domain. Findings from this work may hold important clinical-translational implications for the ASD and FMR1 communities, informing mechanistic intervention targets and diagnostic markers for ASD and FMR1 mutation conditions, paving a pathway toward precision medicine focused on underlying causes of impairment.

NIH Research Projects · FY 2025 · 2024-09

From 2019-2022, telehealth uptake in rural health clinics surged by 73%. This rapid acceleration in telehealth uptake was driven by COVID-19 precautions, the permanent closure of rural hospitals, a massive shortage of mental health professionals, and $1.5 billion in federal investment in broadband access. However, despite the availability and investment in telehealth, many rural patients, especially rural older adults, lack the digital literacy necessary to fully utilize it, exacerbating barriers to quality healthcare and hindering the potential benefits of telehealth in expanding access to quality healthcare. Increasing rurality and older age are associated with lower digital literacy and telehealth adoption, and rural older cancer survivors (ROCS) face compounded risks, which are exacerbated by the reduced access to mental health professionals in rural areas for ROCS experiencing cancer-related distress. Cancer-related distress is stress and anxiety related to a cancer diagnosis and treatment. Telehealth providing support for cancer- related distress is a promising strategy to expand care in rural areas with a shortage of mental health professionals. Still, without interventions to address digital literacy, many ROCS will go without this critical care, thus compromising their overall cancer outcomes. To this end, we developed CONNECT, a web-based toolkit targeting digital literacy and mental health support for ROCS, employing a user-centered design approach and the Designing for Dissemination and Sustainability logic model. CONNECT addresses digital literacy and supports for cancer-related distress management through interactive activities for setting up telehealth visits, accessing educational materials about cancer-related distress, and providing individualized mental health resource recommendations. Feedback from our pilot usability study was positive, reporting high levels of acceptability and usability from users. Yet, additional comments underscored the need to enhance the platform with opportunities to engage caregivers remotely but synchronously to provide additional real-time digital literacy assistance. Building on this pilot, we propose to adapt CONNECT using a co- design process to include recommendations from our pilot, namely, functions that permit synchronous communication with a caregiver (Aim 1). In Aim 2, we will conduct a 2-arm randomized controlled trial to evaluate the efficacy of the adapted CONNECT for improving cancer- related distress among ROCS. We will randomly assign ROCS-caregiver dyads (N=274) to a CONNECT intervention group (N=134) or enhanced standard of care (n=134). Dyads in the intervention group will receive usual care and engage with CONNECT. Participants in the enhanced standard of care group will receive usual care and survivorship care and cancer-related distress literature. Our primary outcome is levels of cancer-related distress. We will secondarily assess digital literacy and healthcare engagement, clinical care, and existing social support networks every 4 months after enrollment for 12 months. In Aim 3, we will use exit interviews in Aims 1 and 2 with a subsample of participants to examine outcomes related to implementation and potential sustainability in the rural multi-level context. Completing these aims will inform future integration of CONNECT across multiple healthcare systems for a multi-site scaled-up RCT.

NIH Research Projects · FY 2026 · 2024-09

Advances in learning health systems (LHS) and implementation science have great potential to address challenges to genetic medicine. We bring together 4 MPIs and a team of investigators with expertise in learning health systems; implementation science; and cardiovascular and cancer genetic medicine to advance our Northwestern genetics-enabled learning health system (Northwestern gLHS). We will design, implement, and continuously refine strategies to enhance genetic medicine in routine clinical care. We are ideally suited to conduct this work for the following reasons. First, Northwestern is a leader in developing an LHS with systems solutions that are continuously refined to improve both healthcare delivery and health outcomes. Northwestern’s established LHS resources and expertise will support our clinical site and the national gLHS network. These resources and expertise integrate our robust clinical, genetic, and patient-reported data capabilities, institutional and community-based electronic health records, and novel web-based tools and technologies to fully realize the promise of the gLHS. Second, Northwestern is a leader in genetic medicine as a member of the Electronic Medical Records and Genomics (eMERGE) consortium and has recruited and effectively integrated genetic results into Northwestern’s EHR as discrete, computable lab values enabling effective clinical decision support. Third, Northwestern’s recent investment in senior implementation scientists, coupled with an established community partnerships with AllianceChicago, a network of community health centers, and Alliance for Research in Chicagoland, a network of non-profit agencies, is poised to lead in implementing and disseminating genetics-enabled healthcare. Our Specific Aims include: 1. Bring together our expertise in learning health systems, implementation science, and genetic medicine to advance our Northwestern gLHS to accelerate the impact of emerging genetic evidence in real-world clinical settings within our health system and community settings. 2. Collaborate with the national network to co-design, implement, and evaluate harmonized projects to create generalizable knowledge that accelerates genetic-based healthcare and improved health outcomes. We propose 3 projects on cascade genetic testing (CGT) for hereditary conditions within cardiovascular disease and cancer as our use case. Our proposed projects each address a different aspect of a challenges in CGT use and over-reliance on probands to convey the importance of CGT to family members. 3. Develop and disseminate gLHS methods to ensure our lessons learned with regard to evidence-based genetic medicine can be scaled across real-world healthcare settings. The Northwestern gLHS methods and tools will guide future wide-scale implementation of CGT and other evidence-based genetics practices within health systems and the community while answering important questions related to implementation of genetic medicine to improve health for all.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Family formation plans (e.g., whether/when to have children) vary by micro-level factors like sociodemographics (age, race/ethnicity) and individual- and couple-level influences like finances and job security. These micro-level influences do not fully account for variations in reproductive life plans, which are also influenced by macro-level factors like state and local laws and structural inequities. Sexual and gender minority (SGM) people's health and wellbeing may be particularly affected by these macro-level factors. Our research and that of others demonstrate that structural stigma (macro-social conditions like anti-LGBT legislation that negatively impact wellbeing) worsens SGM people's mental and physical health. Given current high levels of structural stigma in the US, there is an urgent need to understand the potential health and wellbeing impacts to halt the widening of already gaping health disparities. One aspect of health and wellbeing potentially impacted by anti-LGBT legislation and other forms of structural stigma is having children. Almost 40% of SGM people are interested in parenting but may face unique barriers in doing so. Being unable to freely plan when, whether, and how to have children excludes SGM people from a health-promoting life stage, which may drive some SGM-related health disparities (e.g., alcohol use, cardiovascular health, depression). The proposed mixed-methods study will prospectively examine multi-level impacts on SGM couples' family formation plans. Aim 1. Quantitatively test multi-level influences on family formation plans through a large-scale survey of SGM couples. We hypothesize that couples living in states with higher levels of structural stigma will be less likely to plan to have children and more likely to report that state-level policies influence their decision- making. These associations will be moderated by the racial/ethnic and gender composition of the couple, as well as by SES. Aim 2. Qualitatively describe multi-level factors influencing SGM couples' family formation planning. From the Aim 1 sample, we will recruit couples from states with high and low structural stigma for in- depth dyadic interviews (N=120). We will describe multi-level influences on family formation planning. Aim 3. Given the dynamic sociopolitical landscape for marginalized populations, we will quantify changes in impacts of multi-level factors on family formation plans and well-being over time. We will follow the Aim 2 subsample with dyadic pulse surveys (i.e., brief/regular surveys across three years) and a final in-depth dyadic interview. Using qualitative trajectory methods and prospective analyses of dyadic pulse surveys, we will test our hypotheses that changes (or lack thereof) in couples' contexts (e.g., moving to another state, legislation changes) will influence decision-making, mental health, relationship quality, and family formation. This project will produce the first investigation of how multi-level factors prospectively influence SGM couples' family formation plans. This work will have a positive impact by revealing for the first time the multi-level needs of LGBTQ couples as they form families, thereby informing interventions to reduce entrenched inequities.

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT In the US, high rates of maternal morbidity are urgent public health concerns. Social risk factors, such as low socioeconomic status and limited access to care, critically shape perinatal outcomes, resulting in greater risk of adverse maternal and neonatal health outcomes for low-income women. High-quality antenatal care supports optimal health, yet typically fails to meet the needs of some populations, including those with lower incomes. Improving the health of pregnant women in a patient-centered manner requires innovative models of care delivery across the spectrum of maternal care. One strategy is patient navigation (PN), a longitudinal, barrier-focused, patient-centered intervention that offers support for health services. Although antenatal care is an ideal setting for PN, the benefits of antenatal PN for overall maternal and perinatal health have not been rigorously evaluated in randomized trials. This proposal aims to test the efficacy of an innovative antenatal care PN model that extends and expands care for low-income pregnant women via the Partnering with Antenatal Navigators to Transform Health in Pregnancy (PATH) Trial. We will randomize 550, nulliparous pregnant women with low to receive PN via PATH versus usual antenatal care. Participants randomized to receive PATH will receive intensive, individualized PN services throughout pregnancy. As a multilevel, multidomain, health intervention, PATH is grounded in understanding and addressing approaches to promote self-efficacy, enhance access, support communication, and sustain healthcare engagement. All participants will undergo surveys, interviews, and medical record reviews at 5 study visits from enrollment (<20 weeks of gestation) through 9 months postpartum. Aim 1 will evaluate whether PATH, compared to usual care, improves a composite of maternal adverse outcomes (hypertensive disorders, preterm birth, postpartum hemorrhage, severe maternal morbidity, mortality) and (Sub-Aim 1) healthcare utilization. Aim 2 will evaluate whether PATH, compared to usual care, improves a composite of perinatal adverse outcomes (NICU, low birthweight, small- and large-for-gestational age, perinatal death) and (Sub-Aim 2) healthcare utilization. Exploratory Aims 1 and 2 will evaluate whether PATH’s efficacy varies by different demographic factors (e.g., age). Aim 3 will evaluate patient, clinician, navigator, and health system experiences with PATH, which will be guided by implementation science principles and accomplished via serial collection of patient-reported outcomes, individual interviews, and process mapping exercises. The PATH Trial will fill a significant evidence gap by demonstrating whether antenatal PN among low-income pregnant women, who are disproportionately at risk for adverse outcomes, is an effective strategy to improve perinatal health. PATH represents a critical step in understanding how to improve maternal health, thus achieving an NIH goal.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Age- and function-based positioning of mitochondria plays a critical and conserved role in cellular differentiation and aging from yeast to humans. Evidence suggests that mitochondrial positioning mechanisms selectively transport or retain specific mitochondria based on their fitness, resulting in physiological asymmetry between mother and daughter cells. However, a major conceptual challenge is that mitochondria form connected networks. They experience constant remodeling by mitochondrial fission and fusion, while their size continuously expands during cell growth. The continuous mitochondrial content mixing should eliminate any differences between mitochondria, making it difficult to explain how some mitochondria can be fitter than others. In this proposal, we unite and integrate complementary expertise in mitochondrial biology, quantitative cell physiology, and in silico modeling of organelle dynamics to mechanistically investigate the precise sequence of subcellular events that lead to asymmetric mitochondrial segregation, first during the cell cycle and ultimately to replicative aging. We will implement powerful molecular and single-cell techniques in combination with in silico modeling approaches to control, track, and model individual mitochondria and their dynamics, topology, and function as cells age. The true power and innovation of the proposed research is the tight integration of approaches guided by novel mechanistic hypotheses of cellular aging. In Aim 1, we will test our model for the molecular basis of fitness recognition, which centers on the role of cardiolipin (CL), a lipid linked to myriad mitochondrial functions. We hypothesize that CL both enhances the import of mitochondrial components and is selectively recognized by the mitochondrial transport and tethering proteins, providing a novel testable mechanism for the inheritance of the fittest. We will test whether the tenets of our model enable the emergence of asymmetry in mitochondrial content and function during the cell cycle and, in Aim 2, investigate the impact of that asymmetry on replicative aging. In addition, we will consider the role of other organelles such as the vacuole. We will utilize the yeast mother machine to reveal a hierarchy of age-related changes in mitochondria and vacuoles. The causal relationship between cellular aging and age-dependent changes in mitochondria and the vacuole will be determined. Our studies in yeast will uncover fundamental mechanisms used by cells to establish functional asymmetry within mitochondrial networks. Therefore, this work has the potential to lead to novel therapeutic strategies to slow or reverse aging in humans by manipulating the mitochondrial drivers of aging at the cellular level.