Johns Hopkins University

NIH Research Projects · FY 2026 · 2025-06

The mission of the Johns Hopkins University (JHU) and the University of Maryland Baltimore (UMB) Institute for Clinical and Translational Research (ICTR) Clinical Scholars Research Training Program (K12) is to provide an integrated set of training, research and career development opportunities focused on the core principles of translational science. We will build on our success of training more than 70 junior faculty to date by focusing the scholars’ experience on (1) specific skills for competency in translational research (2) individual mentored project development and (3) community engagement. A core goal of the program is to advance junior researchers in translational science. We have a track record of training scholars in different fields of study and methodologies and will continue to advance this goal. Our history of successful recruitment and selection of a junior group of scholars allows us to build on our efforts to develop a wider range of scholars from various disciplines. Our partnership with University of Maryland, Baltimore allows us to engage with scholars and mentors from multiple disciplines that bring new perspectives to help optimize health outcomes for all. We will use existing strategies to recruit scholars in medicine, nursing, dentistry, public health, pharmacy, engineering and social work with different scientific interests and perspectives in translational science. From a programmatic standpoint we (1) Teach core principles in clinical and translational research, ensuring scholars have the knowledge and skills to succeed in their scientific pursuits and build an identity as translational researchers; (2) Provide a supportive and collaborative culture for scholars; (3) Create a community of clinical and translational science scholars, building networks and collaborations among scholars (and mentors), driving innovation; and (4) Encourage the development of team science skills. Scholars will recognize the importance of working collaboratively, an increasingly critical research skill. Our scholars benefit from an integrated program that offers a multidisciplinary mentoring team, didactic training, competency-based interactive workshops, core ICTR resources, peer-support and resource-sharing designed to stimulate lifelong engagement in a translational research career. The program offers scholars intensive and hand-on learning experiences that prepare them to be exemplary preclinical and clinical translational scientists in any discipline, specialty or subspecialty. Our heterogeneous pool of scholars will emerge equipped with the knowledge, skills, and abilities to advance diagnostics, therapeutics, clinical interventions, and behavioral modifications to improve health and health outcomes as they develop into independent researchers. We will perform continuous scholar, mentor and program evaluation with multiple metrics. We evaluate scholars performance in the program and success after completing the program. Like the consortium of CTSA academic medical institutions, we will report on scholar performance and satisfaction, quality of mentorship and mentor and mentee satisfaction. We will also measure, evaluate, and disseminate the impact of translational research from our program. The JHU ICTR K12 will support 8 clinical scholars, for a minimum of 24 months.

NIH Research Projects · FY 2025 · 2025-06

Project Summary/Abstract Microglia play diverse roles in neurodegenerative disorders such as Alzheimer’s disease, multiple sclerosis, and the motor neuron diseases amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Recent studies have revealed subtypes of microglia with varying molecular signatures and functions, indicating differential responses to stimuli and environmental cues. This heterogeneity suggests that microglia have distinct downstream effects on disease progression. Importantly, breakdown of blood-CNS barriers (BCNSBs; e.g., blood-brain and blood-spinal cord barrier) and leakage of serum proteins into the CNS can activate microglia. However, the identity of these microglial subpopulations and their disease contributions are incompletely understood due to the multifactorial etiologies of many neurodegenerative disorders, where BCNSB breakdown plays only a contributing role. My research aims to characterize specific subpopulations of microglia and determine their contributions to transient receptor potential vanilloid 4 (TRPV4)-mediated motor neuron degeneration. Gain-of-function mutations of TRPV4 causes forms of distal SMA. Recently our laboratory has demonstrated that mutant TRPV4 mice develop severe muscle weakness, motor neuron loss, and lethality due to spontaneous BCNSB opening in the ventral horn of the spinal cord. These deficits can be prevented by genetic ablation of TRPV4 from vascular endothelial cells or pharmacological inhibition of TRPV4. This model provides a unique opportunity to understand the microglial subpopulations activated by BCNSB breakdown in the spinal cord and their role in motor neuron degeneration. In preliminary data, I have observed two distinct, activated microglial populations: one at early disease stages around leaking vessels and another at late stages clustering around degenerating motor neurons. In Specific Aim 1, I will further characterize the spatial patterns of microglia activation in relation to vascular leak and motor neuron degeneration in mutant TRPV4 mice at various time points and following treatment with a TRPV4 antagonist. In Specific Aim 2, I will define the evolution of molecular subtypes of microglia post-BCNSB breakdown using single-cell RNA sequencing. In Specific Aim 3, I will investigate the functional contributions of microglia to BCNSB breakdown and motor neuron dysfunction. By dissecting the interplay between microglial activation, BCNSB dysfunction, and motor neuron degeneration, I aim to unravel mechanisms driving neuroinflammatory degenerative processes in the spinal cord, which might ultimately offer novel therapeutic approaches. This work will not only shed light on the pathogenesis of TRPV4- mediated motor neuron disease, but will offer insights into other neurodegenerative disorders in which BCNSB breakdown triggers neuroinflammation.

NIH Research Projects · FY 2026 · 2025-06

Project Summary Our laboratory is broadly dedicated to understanding the role of protein dynamics while facilitating the engineering of nonribosomal peptide synthetases (NRPSs). Recent structure determination advancements have highlighted that multidomain proteins are often dynamic, exhibiting distinct functional outputs mediated by specific domain interactions. Elucidating the mechanisms underlying how domains transition between these stable interactions remains an outstanding question that must be answered for effectively engineering dynamic multidomain proteins like NRPSs. NRPSs utilize a modular, multidomain architecture to covalently link simple substrates and synthesize complex natural products, many with therapeutic properties (e.g., antibiotics like bacitracin or antitumor agents like epothilones). Swapping domains or modules within NRPSs holds promise for developing improved pharmaceuticals. However, their inherent dynamic nature complicates the interpretation of mutagenesis data obtained through traditional static structures. Engineering NRPSs is thus akin to solving a complex, multidimensional puzzle. To address this challenge, we will combine nuclear magnetic resonance (NMR) spectroscopy and computational approaches to determine structural ensembles that enable the prediction of how mutations affect protein functions by altering their dynamics. Furthermore, we will initiate single-molecule studies to link these intra-domain changes to inter-domain communication, enabling a holistic interpretation of product formation assays. Our results will identify key residues that must be modified to alter substrate and domain recognitions and also to maintain functional dynamics during NRPS engineering. Leveraging over 20 years of expertise in NMR protein dynamics and large protein studies, we will collaborate with specialists in all other relevant areas to ensure the success of this research. Our findings will pave the way for effective NRPS engineering, facilitating the development of novel therapeutics. Additionally, our work will offer a valuable paradigm for understanding how dynamic multidomain systems remodel domain interactions to regulate function, a ubiquitous phenomenon across biological systems.

NIH Research Projects · FY 2026 · 2025-06

Cognitive impairment is a common symptom in aging and associated neurological disorders such as Alzheimer’s disease (AD) and dementia, significantly reducing quality of life and causing a heavy burden on our health care system and society in general. Associations between obesity and impaired cognitive function and risk of dementias have recently been recognized. Obesity in mid-life is a predictor of mild cognitive impairment in old age. However, there is still no non-invasive biomarkers for early diagnosis and treatment evaluation of cognitive impairment, including obesity-linked cognitive impairment. Investigation of the pathophysiological changes in obesity-linked cognitive decline is critical for development of sensitive biomarkers and effective interventions. To this end, magnetic resonance imaging (MRI) as a non-invasive neuroimaging technique is a powerful and versatile tool. Cerebral neurovascular abnormalities have been associated with obesity-linked neurological disorders and may contribute to loss of neurons and memory deficits. We recently developed several new MRI techniques that provide non-invasive approaches to assess neurovascular and lymphatic changes, neuroinflammation and blood brain barrier (BBB) integrity in both human and animal brains. Our preliminary data shows that there is a significant memory deficit in obese SP1 transgenic mice corresponding with abnormal neurovascular and lymphatic changes measured by MRI. Thus, we propose to test the hypothesis that obesity induces neurovascular and lymphatic abnormalities and BBB dysfunction in the brain that may contribute to cognitive impairment and its related pathology. Using newly developed MRI methods, we will determine whether any of these abnormalities may be indicators for obesity-linked cognitive decline using a human synphilin-1 (SP1) obesity mouse model and a high-fat diet-induced obesity mouse model. These MRI measures will be validated with histological methods and will be correlated with pathological and cognitive impairment. Aim 1: We will assess abnormalities of small blood vessels in the brains. Aim 2: We will assess abnormalities in the cerebral perivascular space and lymphatic vessels in the brains. Aim 3. We will assess BBB integrity and neuroinflammation in the brains. Aim 4. We will study interactions among the abnormalities in cerebral blood and lymphatic vessels and BBB dysfunction and identify composite MRI markers for the pathogenic process of obesity-linked cognitive impairment. These studies will reveal obesity-induced neurovascular and BBB alterations in brains that are associated with cognitive impairment corresponding to pathological and behavioral changes. Outcomes of these studies will provide novel insights into the neuropathological changes underlying obesity-linked cognitive impairment, and thus may facilitate development of biomarkers for early diagnosis and intervention evaluation, and potential treatment targets for obesity-linked cognitive impairment and other dementia.

NSF Awards · FY 2025 · 2025-06

Separating chemical mixtures into their individual components is often the most energy-intensive step in chemical manufacturing. More efficient separation and purification methods could reduce energy demands and costs of chemical production. Highly selective membranes can separate complex gas mixtures at low cost and high energy efficiency. Zeolites are crystalline materials with arrays of pores that separate gas molecules based on their size, shape, and interactions with the pore walls. Zeolites are exceptionally well-suited for use as industrial gas separation membranes due to their excellent selectivity and chemical and thermal stability. Zeolite membranes have been commercialized for a few applications, but synthesizing thin zeolite films cost-effectively remains challenging, which limits their practical use. This project will develop a new type of zeolite membrane consisting of very thin sheets of a zeolite with pores small enough to perform difficult gas separations such as separating ammonia from hydrogen and nitrogen. The project is an international collaboration between Johns Hopkins University, USA, and Ecole Polytechnique Federal de Lausanne, Switzerland. It will generate new fundamental knowledge necessary for innovation in the multi-billion-dollar global molecular separations market, increasing U.S. and Swiss economic competitiveness in critical industries. This project will investigate a scalable approach for synthesizing selective zeolite membranes on porous supports. Specifically, zeolite nanosheets – high-aspect-ratio two-dimensional (2D) zeolite crystals possessing pores with eight-member-ring (8-MR) apertures – will be used as building blocks for preparing gas-selective membranes. Exfoliated zeolite nanosheets with the 8-MR pores orthogonal to the lateral dimension of the layer have not yet been synthesized. The project aims are to (i) synthesize highly crystalline, intergrowth-free, and high-aspect ratio 8-MR layers, (ii) exfoliate the 8-MR layers, (iii) deposit thin films on hollow fiber supports, and (iv) prepare graphene-supported nanometer-thick films. The study includes the development of novel zeolite nanosheet synthesis approaches combined with state-of-the-art thin film assembly, microstructural characterization, and membrane performance testing. This work will produce processing-structure-function relations for nanoporous thin film membranes. Fundamental knowledge will be gained about nanoporous materials synthesis, multiscale assembly at interfaces, and gas transport in complex microstructures. This collaborative U.S.-Swiss project is supported by the U.S. National Science Foundation (NSF) and the Swiss National Science Foundation (SNSF), where NSF funds the U.S. investigator and SNSF funds the partners in Switzerland. 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 2026 · 2025-05

PROJECT SUMMARY Type I spiral ganglion neurons (SGNs) are the sensory afferents of the inner ear that form ribbon synapses with mechanosensory inner hair cells (IHCs). Each IHC is mono-synaptically innervated by up to 30 SGNs with ribbon synapses on single IHCs forming highly stereotyped gradients of varying properties that correlate with the position of these synapses along the basolateral surface of the cell. The mechanisms that regulate the formation of synapses with different properties and localizations along the basolateral axis of single IHCs are not known. Taking advantage of recent single cell RNA sequencing data sets generated by us and others, I am now able to rigorously test the molecular mechanisms guiding the development, refinement, and function of IHC ribbon synapses. Based on recent studies and my preliminary data, neurexin 3 (NRXN3) stands out as a potential regulator of synapse formation between IHCs and SGNs. In this study I propose to investigate NRXN3 as a potential contributor to IHC-SGN synapse formation using mutant mouse models conditionally lacking Nrxn3 with established assays of in situ hybridization, immunostaining, electrophysiology, electron microscopy, and auditory brainstem recordings. I anticipate that loss or mutation of NRXN3 contributes to the molecular pathogenesis of hearing deficits in humans.

NIH Research Projects · FY 2026 · 2025-05

Across the USA the incidence of new HIV infections continues at a high level with 49% of all new HIV infections between 2018-2022 occurring in the southern region of the USA. With antiretroviral therapy people with HIV (PWH) are aging, with 72% in the USA stating that they feel healthy. However, age-associated conditions including neurologic and neuropsychiatric disorders, cardiovascular disease, liver and kidney disorders, osteoporosis, specific cancers, and metabolic dysfunction continue to be challenges for a significant proportion of PLWH. A biomedical workforce trained in the principles of foundational basic and clinical research is needed to address these ongoing challenges. Those armed with the research skills and education can help advance basic science findings through the preclinical research pipeline, and ultimately to bedside practice thereby, improving human health. Over the last five years, our research-intensive training program focused on the neurologic and mental health impacts of HIV infection for undergraduates, exceeded our goal by 40% in the total number trained. Thirty-nine percent have matriculated to graduate-, medical-, or nursing school, or are employed as research scientists in academic laboratories. Forty-three percent continue as juniors or seniors in college with majors in neuroscience, or the biological sciences. Several are published authors, with additional publications expected. In total, 82% of participants remain on target to pursue advanced graduate degrees and remain engaged in basic or clinical research. The purpose of the proposed training program is to significantly increase the persistence, and hasten the career progression of undergraduates and masters level students to graduate level training in neuroHIV or closely aligned research area. Participants will be engaged with program staff and their mentors over one-year using a combination of virtual and in-person training tools. The trainee’s experience will culminate with their 10-week in-person research intensive and presentation at a campus-wide scientific symposium. The year-long engagement will foster a sense of community among trainees within their lab groups and among program participants overall. We fully expect that with productive interactions, irrespective of the outcomes of their research, program alumni, armed with their newly acquired scientific know-how, social capital and resources, we expect that the long-term goals of the proposed training will endure far beyond the confines of the program.

NSF Awards · FY 2025 · 2025-05

This Partnerships for Innovation - Technology Translation (PFI-TT) project develops of a remote monitoring system to reduce the morbidity and mortality associated with infections among patients undergoing peritoneal dialysis (PD). PD removes excess fluid and toxins while correcting electrolyte imbalances in people with kidney failure. This project will develop a medical device with the potential to increase PD treatment access for affected patients in rural areas. This technology will enable high-frequency measurement of cellular biomarkers, providing a novel platform for advancing scientific understanding of infection evolution, immune response, and infection treatment efficacy. Ultimately, the development and commercialization of this technology may make at-home PD accessible to patients living with end stage renal disease, significantly improving their quality of life. The project will enable the real-time microscopic analysis of large volumes of unmodified dialysate flowing through a catheter, reducing the time to infection diagnosis. Completion of the research objectives will result in a system capable of real-time, continuous, and quantitative monitoring of numerous biomarkers relevant to PD-associated infections. To develop this technology, the team will: (1) use simulation models to optimize the optical and flow chamber design parameters for high-resolution and high-throughput characterization of flowing dialysate; (2) construct a benchtop prototype system and characterize the performance using fresh dialysate titrated with relevant biomarkers; and (3) prepare a prototype, analysis algorithm, and protocol for testing discarded dialysate samples. A commercial medical device based on the technology would enable high-frequency at-home screening for dialysate infections, substantially reducing the time to detection and diagnostic confirmation of infection. 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 · 2025-05

Project Summary The GBCC2025 conference, "Genomic Data Science and Beyond with Galaxy and Bioconductor," aims to bridge the gap in integrating genomic data, tools, and communities. With the rapid advancements in genomic science generating an ever-increasing volume of data and analysis methods, there is a critical need for robust, accessible tools and collaborative platforms to facilitate data analysis and interpretation. Despite significant progress, substantial gaps remain in fostering environments where new analysis methods are readily developed, incorporated, and utilized, hindering the ability to achieve medical breakthroughs that improve human health. Galaxy’s user-friendly web platform and Bioconductor’s comprehensive suite of R-based genomic data analysis tools offer complementary strengths that, when combined, provide powerful, unified solutions for the genomic research community. This joint conference will enhance interoperability, promote innovative workflows, improve training and education, enrich documentation efforts, and ultimately accelerate discoveries in genomic science. The specific aims of the GBCC2025 conference are to: 1) Foster collaboration and innovation in genomic data science by organizing sessions that demonstrate the integration of Bioconductor tools into the Galaxy platform, enhancing interoperability and streamlining data analysis workflows; 2) Enhance training and education by offering structured training opportunities and hands-on workshops, including collaborative tutorials; and 3) Strengthen community and networking among genomic researchers by facilitating unified poster sessions and shared community networking events. By addressing the critical need for integrated genomic data, tools, and communities through these aims, the GBCC 2025 conference will enhance collaboration, improve training and education, and strengthen the genomic research community, ultimately accelerating discoveries in genomic science and contributing to medical breakthroughs that improve human health.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Despite the effectiveness of antiretroviral therapies, virologically suppressed people with HIV (vsPWH) are at a higher risk for comorbidities such as neurocognitive, neuropsychiatric, and sleep disorders. Notably, 50-70% of vsPWH experience symptoms of insomnia, including trouble falling or staying asleep, poor sleep quality, and low daytime energy levels—rates 2.5 times higher than the general population. This exacerbates their health burden significantly. Sleep disorders and inflammation are linked. Sleep disturbances can trigger inflammation, and systemic inflammation may lead to neuroinflammation, disrupting sleep patterns. In vsPWH, elevated CNS inflammatory markers and distinct microglial activation suggest that microglia-mediated neuroinflammation could underlie HIV-related sleep deficits. Nonetheless, the microglial molecular landscape and its role in sleep phenotypes in murine NeuroHIV models remains understudied. Another line of research highlights the importance of microglia in regulating extracellular glutamate in the brain, a neurotransmitter linked to HIV- induced neurocognitive deficits. Glutaminase (GLS1) is the primary enzyme for glutamate synthesis and is upregulated in activated microglia. Using our brain-penetrable GLS1 inhibitor, JHU-083, we have shown that inhibiting microglial GLS1 improves cognitive deficits in disease models of neuroinflammation, including the EcoHIV-infection murine model of HIV. More recently, we found that EcoHIV-infected mice exhibit decreased sleep amount in the early rest period and increased sleep fragmentation, similar to what has been reported in vsPWH, and that JHU-083 could attenuate these deficits. Thus, we hypothesize that increased microglial GLS1 activity contributes to HIV-induced sleep disturbances, and inhibiting microglial GLS1 will alleviate sleep deficits. We will take the following steps to explore this understudied area of research: 1) characterize the sleep phenotypes in two murine NeuroHIV models - HIV-infected hu-BLT-hIL34 mice and EcoHIV-infected C57BL/6J mice using the piezoelectric sleep recording system and EEG; 2) characterize microglia activation, neuronal activity, neuroinflammation, and microglial transcriptome in the two NeuroHIV models and 3) determine whether selective inhibition of microglial GLS1 using a hydroxyl dendrimer-GLS1 inhibitor delivery system will ameliorate HIV-induced sleep deficits and normalizes microglia activation and neuronal activity change, neuroinflammation, and inflammatory/sleep-related microglia molecular signatures. Successful completion of these goals will lay the groundwork for developing novel mechanism-based therapeutics targeting sleep disturbances in vsPWH.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Hidradenitis suppurativa (HS) is a chronic inflammatory disease that significantly reduces quality of life due to debilitating skin lesions and scarring. HS may be caused by a single gene mutation, most commonly in the nicastrin (NCSTN) subunit of the γ-secretase (γS) protease complex, which regulates substrate access to γS. In a majority of patients with acquired HS, there is no identifiable mutation, yet they suffer an identical clinical phenotype to monogenic HS. While HS has historically been understood as a disease of keratinocytes, recent discoveries have identified dermal fibroblasts as important loci of inflammatory signaling in HS skin. Further, NCSTN is decreased in dermal fibroblasts of acquired HS patients, which may drive aberrant immune signaling from these cells. These findings support the global hypothesis that acquired HS phenocopies monogenic HS due to shared loss of NCSTN and subsequent γS dysregulation. However, the enzymatic activity of γS in HS patients, as well as the factors which drive NCSTN loss, remain exciting areas of future discovery. Epidemiological studies suggest that cases of acquired HS have been increasing over the past 3 decades. Given well-characterized clinical data that HS only occurs post-puberty and improves with hormone-modifying medications, this increase is likely to be driven in part by an environmental factor. Additional data suggests that in acquired HS, both skin lesions and fibroblasts cultured ex vivo have high levels of plastic-associated endocrine disruptors (pEDs) compared to healthy controls and that NCSTN protein expression in fibroblasts is decreased by exposure to physiologically relevant concentrations of pEDs. To address these questions, I plan to define the enzymatic activity of γS and regulation of NCSTN expression in HS fibroblasts and in pED exposure. My preliminary analysis indicates that γS proteolytic activity is decreased in HS fibroblasts for a specific substrate, which may drive downstream inflammatory pathways. In this project, I will test the hypothesis that that γS kinetics and NCSTN regulation in HS fibroblasts differ from healthy controls and that treatment of normal fibroblasts with pEDs will phenocopy HS. I will quantify γS activity using a Förster resonance energy transfer (FRET) assay and characterize changes in inflammatory cytokines using functional in vitro studies. In parallel, I will also characterize the regulation of NCSTN protein expression and identify major regulatory networks in HS and pED exposure by analyzing chromatin accessibility and gene expression through single-cell ATAC and RNA sequencing. With these studies, I hope to define the role of γS activity and NCSTN regulation in HS. Further, I aim to definitively clarify the role of pEDs in HS through rigorous studies. Understanding these relationships could have important implications for the treatment and management of HS and other diseases with γS dysfunction.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY The objective of this project is to develop and apply statistical methods to improve scientific inferences in Alzheimer's disease (AD) research when cross-sectional or longitudinal study designs are employed. The proposed approaches are largely motivated by three large-scale studies (BIOCARD, ABC-DS, PAC) to study AD, but can also be applicable to study other chronic diseases. The study team plans to de- velop efficient and statistically proper methods to better model, estimate, and predict the risk of disease incidence and longitudinal biomarker outcomes. The proposed approaches will help identify individuals who are at a high risk of experiencing incidence of disease (MCI or AD) so that these individuals can be targeted for more intensive monitoring or treatment. The proposed research includes the following aims: Aim 1: to develop statistical methods to handle age-specific prevalent cases in case-control stud- ies. Prevalent AD cases identified from cross-sectional populations are frequently sampled and included in case-control data. When adopting such a sampling design, survivor bias could form a serious problem to lead to biased analysis results. Existing approaches typically treated cases and controls in binary form without specifying age at incidence of disease, and the prevalent cases are sampled with length bias sam- pling in stationary models. Instead of binary disease outcome, we consider age-specific risk outcome and propose a composite likelihood approach which handles survival bias in either stationary or non-stationary models. Aim 2: to develop regression methods for analyzing age at biomarker positivity and the remaining time to onset of clinical symptoms. In some longitudinal studies of AD, MCI-free subjects are recruited for follow-up of the subsequent development of AD-related clinical symptoms. Meanwhile, age at biomarker positivity, a crucial characterization of the stage of biomarker deterioration, is of interest and retrospectively identified. This type of recruitment creates a special sampling structure that we refer to as partial left truncation. Under Aim 2, we will develop estimating equation methods and computa- tional techniques that correct the sampling bias in the presence of competing risks due to death without disease, and study a bivariate failure time model to analyze age at biomarker positivity and the remain- ing time to onset of clinical symptoms of MCI. Aim 3: to develop statistical methods for biomarker trajectories prior to onset of clinical symptoms. AD biomarkers often undergo changes years before the emergence of clinical symptoms. Existing studies often model biomarker trajectories using a forward time scale such as age and time since study baseline. Trajectory models are proposed to examine the changes and trend of biomarkers prior to the onset of clinical symptoms. We propose semiparametric procedures to estimate the marker trajectories stratified by the age at onset of clinical symptoms and the type of failure events, in the presence or absence of knowledge on the shape of the trajectory.

NIH Research Projects · FY 2025 · 2025-05

More than 6.5 million persons are living with Alzheimer’s Disease and Related Dementia (ADRD) in the United States, most of whom reside in the community. ADRD’s progressive and disabling nature necessitates increasing assistance as the disease advances. Thus, people living with ADRD rely on medical and social services provided in home- and community-based settings (HCBS) to age in place and maintain quality of life. Without a universal long-term care insurance program, most HCBS is paid for out-of-pocket or by Medicaid. Almost all states use Medicaid HCBS waivers to expand services offered and eligibility criteria under the assumption these services will help individuals avoid/delay institutionalization and remain living independently in the community. Medicaid plays a key role in funding HCBS for people with ADRD as well as developing innovative HCBS care models. Medicaid HCBS waivers characteristics vary significantly, yet these differences are not well documented. The lack of data about Medicaid HCBS waiver characteristics impedes rigorous evaluation of the effectiveness of these waivers on keeping PLWD at home, e.g. time spent at home. We have developed a methodology to construct an automated reproducible, updateable, national, longitudinal dataset with comprehensive data on Medicaid HCBS waiver characteristics from waiver application documents that will be shared publicly. Our long- term goal is to examine the comparative effectiveness of Medicaid HCBS waiver programs to improve quality of life for PLWD and to inform the creation of evidence-based, quality measures of HCBS. As a necessary step to support this goal, our objectives are to establish a validated methodology to catalog HCBS waiver characteristics and to describe users of waivers by ADRD diagnosis in a population of adults age 65+. Specifically, we will first validate a comprehensive methodology to assess Medicaid HCBS waiver characteristics. Second, we will examine the relationship between Medicaid HCBS waiver characteristics and days spent at home for people with ADRD. By linking waiver characteristics with individual-level claims, we will begin to understand what aspects of waivers impact time spent at home for people with ADRD. Consequently, this will allow for meaningful investigations into the comparative effectiveness of Medicaid HCBS waivers to promote high quality care for people with ADRD and the other 7+ million Medicaid HCBS recipients nationally. This work aligns with themes from the NIA National Research Summit on Care, Services, and Supports for Persons with Dementia and Their Caregivers and directly advances the NIA’s Strategic Directions for Research goal to “support the development of population-based datasets, especially from longitudinal studies, suitable for analysis of biological, behavioral, and social factors affecting health, well-being, and functional status through the life course.”

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Neuroinflammation, particularly triggered by amyloid-β (Aβ) aggregates, plays a pivotal role in Alzheimer’s disease (AD) pathophysiology. Despite significant research, the precise mechanisms underlying Aβ oligomer (Aβo)-induced microglial activation and neurotoxicity remain elusive. Our study aimed to fill this gap by investigating the involvement of the NOD2/RIPK2 signaling pathway in neuroinflammation and neurodegeneration in AD. Utilizing Stable Isotope Labeling with Amino acids in Cell culture (SILAC) combined proteome analysis, we identified RIPK2 as a key mediator of Aβo-induced microglial activation. We observed substantial accumulation of NOD2 and RIPK2 proteins in the hippocampal tissues of AD patients, supporting their pathological relevance. Furthermore, we demonstrated the interaction between Aβo and NOD2 leading to NOD2/RIPK2-mediated neuroinflammatory responses via MAPK and NF-kB activation in microglia. Building on these findings, our study aims to characterize the role of NOD2/RIPK2 signaling in AD and explore its therapeutic potential through molecular and biophysical assessments. Additionally, we will investigate the effects of selectively removing microglial NOD2 and RIPK2 and pharmacologically inhibiting RIPK2 on Aβo-induced pathology, neuroinflammation, and neurodegeneration in AD mouse models. These insights could pave the way for novel AD treatments targeting microglial NOD2/RIPK2 signaling. In Aim 1: To elucidate the mechanisms driving microglial activation by Aβo and assess the involvement of NOD2/RIPK2 signaling, we will conduct detailed molecular and biophysics analyses. Our preliminary findings indicate significant NOD2 and RIPK2 accumulation in the hippocampus of AD postmortem tissues, suggesting their role in Aβo-induced microglial activation. We will explore the binding kinetics and domain in Aβo-NOD2 interaction and its downstream effects on microglial activation pathways, including RIPK2-mediated ubiquitination and NF-kB activation. In Aim 2: To determine the impact of selectively removing microglial NOD2/RIPK2 signaling on microglia activation and neurodegeneration in AD, we will utilize genetically modified AD mouse models. By generating 5xTg mice with microglia-specific NOD2 or RIPK2 depletion, we aim to assess their specific contributions to Aβo-induced pathology. Behavioral tests, plaque assays, synaptic dysfunction analysis, gliosis evaluation, neuronal loss assessment, and characterization of disease-associated microglia populations will be conducted at 8 months to comprehensively evaluate neurodegenerative changes. In Aim 3: Building on our promising findings with the RIPK2 inhibitor CMPD0673, we will investigate its neuroprotective effects in AD. Oral administration of CMPD0673 to 5xTg mice will be conducted for 4 months, followed by comprehensive assessments at 8 months. Behavioral tests, plaque assays, synaptic function analysis, gliosis evaluation, neuronal loss assessment, and characterization of disease-associated microglia populations will be performed to evaluate the efficacy of RIPK2 inhibition as a potential therapeutic strategy for AD and related dementias.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY This project aims to enhance the health and well-being of individuals transitioning from correctional facilities to community settings by addressing barriers to accessing and engaging in medications for opioid use disorder (MOUD) treatment using an innovative complex systems approach. A complex systems approach aims to address social determinants of health and expressly acknowledges that achieving health equity requires more than just individual interventions; it necessitates systemic changes that improve coordination, communication, and resource allocation across various organizations and agencies involved in the reentry process. This approach focuses on transforming the interconnected components of the reentry system to create a supportive environment that facilitates continuous and effective access to MOUD treatment. Specific aims include: 1) examination of the structure and function of organizational networks and strength of relationships among organizations that provide reentry and linkage services for MOUD treatment, 2) provider perspectives on how network connectivity and multi-level interactions impact linkage for MOUD treatment, and 3) perspectives of formerly incarcerated individuals with current or prior illicit opioid use on interactions with the complex reentry system for linkage to MOUD treatment. The research design employs a multi-method approach, combining quantitative and qualitative data collection and analysis. Quantitative data will be collected from organizational leaders and reentry service providers using a network survey consisting of a network inventory and a relational coordination assessment. Qualitative data will be gathered through in-depth interviews with reentry service providers and formerly incarcerated individuals, focusing on their experiences with access and linkage to MOUD treatment. The project will utilize complex systems and organizational network analysis to understand the structure and dynamics of reentry organizations involved in MOUD linkage and treatment. The findings will inform the development of policy recommendations and intervention strategies aimed at improving the coordination and integration of reentry services. This research is highly relevant to the mission of the National Institute on Drug Abuse (NIDA) as it addresses critical gaps in the provision and care continuity of MOUD, which is essential for reducing opioid-related morbidity and mortality among populations with criminal legal system involvement. By focusing on the systemic and organizational factors affecting MOUD access, this project seeks to create a more effective and equitable reentry system that supports the health and recovery of formerly incarcerated individuals.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Abstract The long term objective of the proposed research is to enhance healing after injury that is often slow and incomplete. We hypothesized that injury to epithelial tissue like skin and gut share commonalities in healing, with some native injury responses which actually restrain healing. The goal of this grant is to define the mechanism of this restraint in hopes of developing therapies to enhance healing. We will test if inhibition of these pathways that restrain healing can improve regeneration after injury or infection to the gut or skin in the hopes of suggesting a new class of therapeutics to aid healing from diverse injuries.

NIH Research Projects · FY 2025 · 2025-05

Project Summary: Over the past decade, the capacity of electrophysiology has risen 5-10X driven in large part by the introduction of Neuropixels 1.0 in 2017. The addition of the smaller 384 channel Neuropixels 2.0 probe in 2023 enables facile chronic use, 2 probes with the head stage weighs less than 1.3 grams. The pending introduction of the 1536 channel probe Neuropixels 2.0 QuadBase in Q2 2024 followed by the Neuropixels 2.0 size 1536 channels Neuropixels NXT Probe (developed entirely with support from NIH U01 NS115587) will add to the more than 1200 labs using Neuropixels. All these probes are sold by the fabricator, imec, at cost with no support. To date the principal support channels have been the Neuropixels Slack channel, once annual classes through an expired Wellcome Trust grant at University College London and an expiring U24 at the Allen Institute (U24 NS109043). The development consortium for Neuropixels 1.0 and 2.0 do an annual survey to understand community needs. The leading request from this survey is more classes. This application will provide at least 4 classes per year for at least 12 students per class. The classes with emphasize hands on experience and practice, with the object that the students have enough experience to return to their home labs with the knowledge to setup and record from live animals with Neuropixels and analyze the data they produce. The class will not teach rodent surgery, but a demonstration of chronic implants will be offered for at least once per year. The advent of pinpoint surgery planning, now integrated into SpikeGLX and OpenEphys recording software will regularize and speed multiprobe insertion experiments. Equally critical to data generation, relatively simple once the anxiety for handling Neuropixels probes is contained, is data digestion and interpretation. A simple two probe Neuropixels NXT recording will generate nearly a 1 TB (terabyte)/hour. Digestion and understanding of such large data sets require a fundamental shift in data management and information extraction. This process will be in hand by the teaching labs but will evolve quickly over the timeline of this application. Students will analyze data they generate during the class. We will evolve the content of this segment of our course as the methods and tools evolve over the 5 years. More than one of the host labs maintains activity in data analysis pipeline creation and spike sorting evaluation This project will provide support for the Neuropixels Slack channel (current users number ~4,400) and a suite of online free instructional videos for all the Neuropixels systems including the OneBox recording system expected in Q2, 2024. All lectures will be archived for online viewing on the NeuropixelsCentral YouTube channel. Critical for a 5 year timeline in a space evolving as fast as high channel electrophysiology will be to evolve the course content and recruit instructors at the forefront of the subject. That the host groups are large volume Neuropixels users will ensure content remains current.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY/ABSTRACT Lyme disease is the most common vector borne disease in the northern hemisphere, causing nearly 500,000 cases in the United States alone each year. This disease is caused by the spirochete Borrelia burgdorferi, which is transmitted to humans by the bite of an infected Ixodes tick. To persistently infect a host, B. burgdorferi must transmit from a tick, colonize the initial site of infection, and disseminate to distal tissues. Each stage of the infection cycle provides different environmental pressures, so the spirochetes undergo stage-specific transcriptional regulation to express genes required for their survival. I have recently discovered that epidermal growth factor (EGF) may be an environmental cue recognized by B. burgdorferi to coordinate this stage-specific gene expression. In my preliminary data, EGF directly bound to the spirochetes and induced a B. burgdorferi transcriptomic profile consistent with what is seen at later stages of infection. This is the first description of B. burgdorferi directly binding to a host protein to coordinate gene expression. However, the binding of EGF to B. burgdorferi and the resulting transcriptional regulation remains poorly characterized. Here, I aim to characterize binding by estimating the binding kinetics and specificity with flow cytometry and surface plasmon resonance, and by determining the spatial dynamics with immunofluorescence and electron microscopy. Further, I aim to dissect EGF-mediated transcriptional regulation by comprehensively characterizing the B. burgdorferi transcriptome following EGF treatment, and by identifying responsible transcription factors through the use of transcription factor knockout B. burgdorferi strains. Overall, the work proposed here will immediately expand our understanding of B. burgdorferi host sensing, identify a vulnerable interaction, and establish an exciting new paradigm by which the direct binding of a host protein impacts the coordination of B. burgdorferi gene expression. Further, it will lay the foundation for future studies to increase our understanding of Lyme disease pathogenesis, and result in powerful new treatments and therapeutics to limit the public health burden of this disease. Under this K22 award I will work with my mentors and collaborators to develop the expertise needed to successfully execute the bacterial transcriptomic and imaging studies detailed here. Further, I will attend career development workshops and work with my mentors to develop the skills needed to build my own grant-funded research program at a leading academic institution. Overall, this proposed K22 award will provide me with the time and structure needed to train and develop professionally so that I may meet my career goal of becoming an independent investigator focusing on host-pathogen interactions shaping vector borne disease pathogenesis.

NIH Research Projects · FY 2025 · 2025-05

1 Project Summary 2 The proposed research aims to identify the drivers of women’s sexual and reproductive empowerment, including 3 male influences and subsequently demonstrate the predictive effect women’s SRH empowerment as a 4 mechanism to reduce unintended pregnancies by increasing their ability to better align their reproductive 5 intentions and behaviors. The project takes place in Burkina Faso, a high fertility and highly patriarchal country 6 in West Africa. It leverages existing data from the Performance Monitoring for Action (PMA) project, which 7 collects nationally representative longitudinal data on a range of SRH measures, including a validated SRH 8 empowerment scale. PMA currently includes 3500 partnered women of reproductive age who responded to four 9 annual surveys between 2019 and 2024. The project will expand the PMA female panel by adding a male 10 component, developed using a sequential mixed model design, including 1) a qualitative study among 120 adult 11 men in 4 communities in Burkina Faso, 2) cognitive interviewing and pilot testing of a novel SRH male module 12 derived from the qualitative study and 3) two new rounds of PMA panel data among 4500 couples, to enrich the 13 understanding of women’s SRH empowerment through a gender lens. Our specific aims are three-fold: 14 Aim 1. Evaluate short- and long-term changes in SRH empowerment and identify predictors of these 15 changes. we will use latent trajectory model and linear growth modeling to identify sociodemographic and life 16 events that predict yearly and long-term changes in SRH empowerment scores based on 4 rounds of existing 17 PMA female data. 18 Aim 2. Understand and evaluate men’s influence on women’s SRH empowerment. We will conduct a 19 qualitative study and use thematic analysis to understand men’s perspectives on childbearing and contraceptive 20 decisions. Findings will inform the development of a new male SRH module, that will be pretested and added to 21 the existing PMA female panel. We will use linear regression models to evaluate men’s influence on the 22 development and exercise of women’s SRH empowerment across the reproductive life span using couple linked 23 data. 24 Aim 3. Evaluate the effect of SRH empowerment on reproductive intentions and behaviors, accounting 25 for men’s influences. Adding an additional round of PMA couple data, we will employ generalized estimating 26 equation models to assess the predictive effect of women’s SRH empowerment in reducing the intentional gap 27 between fertility and contraceptive intentions and the behavioral gap between contraceptive intentions and 28 behaviors. We will also examine if male and couple factors change these associations.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY CD8+ T cells are a critical component of the adaptive immune system and play an essential role in immune defense against viruses, bacteria, and tumors. To achieve such a critical function in many different contexts, CD8+ T cells have evolved to be highly adaptive by modulating cellular metabolism. Activated effector T cells require high metabolic flux through anabolic growth-promoting pathways, while quiescent or more resting states engage catabolic processes for ATP generation. After prolonged antigen exposure, CD8+ T cells can become dysfunctional as they enter a distinct differentiation state known as T-cell exhaustion. This dysfunctional state of T cells is characterized by stable expression of inhibitory surface receptors, poor response to tumor antigens, and low cell proliferation and persistence of T cells in vivo, dampening immunity and causing poor responsiveness to immune checkpoint inhibitors. Growing evidence indicates that exhausted T cells are ‘metabolically insufficient’ with altered signaling cascades and transcriptional and epigenetic landscapes. Metabolites are not simply byproducts of the differentiation of T cells, but metabolism itself may dictate T cell exhaustion. Hence, modulating metabolism might reprogram or rewire certain states of T cell differentiation. However, how metabolic rewiring drives and defines the differentiation of T cell exhaustion remains unclear. We applied an untargeted liquid chromatography-mass spectrometry-based metabolomics approach and found exhausted T cells display a distinct metabolic profile compared to functional effector T cells. We thus hypothesize that chronic TCR stimulation imposes unique constraints on T cell metabolism that can be targeted to reinvigorate exhausted T cells by overexpressing metabolic genes. Encouraged by a striking metabolic difference between exhausted T cells and effector T cells, we will use unbiased genetic and systems approaches to understand the functional relevance of metabolic pathways in CD8+ T cell immunity. Several loss-of-function (LOF) screen studies have recently identified that remodeling metabolism is intrinsically linked to cellular development, activation, function, differentiation, and survival in T- cell biology. However, the comprehensive discovery of regulators requires both gain-of-function (GOF) and LOF approaches. In Aim 1, we performed a functional genomic screen in vitro using a metabolism-focused CRISPR activation library to identify potential gain-of-function metabolic targets that limit T cell persistence. In Aim 2, we will determine the molecular mechanism by which the newly revealed GOF candidates reinvigorate T cell exhaustion. The interactive analysis of the collected data will allow us to define the molecular mechanisms by which metabolic pathways regulate T cell exhaustion. Collectively, we hope that our work will provide insight into how to therapeutically modulate metabolism to restore exhausted T cells.

NIH Research Projects · FY 2026 · 2025-05

Project Summary The long-term goal of our lab is to understand gene regulatory mechanisms that enable the development of a single cell zygote into a multicellular organism. This proposal focuses on an essential mechanism in all animals, the post-transcriptional repression by microRNAs. MicroRNAs (miRNAs) repress target genes, controlling their protein output in time and space. They provide an essential layer of regulation during development, evidenced in the fact that loss of the machinery that processes these short RNAs causes embryonic lethality in every animal examined. Moreover, mutations in the miRNA biogenesis or effector machinery in humans causes syndromic diseases. Individual miRNAs have also been linked to essential functions in model organisms as well as disease in humans (e.g. mutation in a single miRNA causes progressive deafness in humans). Although the number of miRNAs has increased during animal evolution, a set of 32 miRNAs were present in the last common ancestor of bilaterian animals and have been conserved over hundreds of millions of years. However, with few exceptions, the functional targets of these highly conserved miRNAs remain unknown due to a number of technical challenges associated with: i) the short nature of miRNAs that has made their profiling more difficult than longer mRNAs, ii) the fact that miRNAs exert quantitative, often modest, repression on their targets, and iii) the fact that target predictions that largely rely on short sequence information, produce an excess of false positives. Our research program systematically tackles the roles of conserved miRNAs during animal development. We have developed a research strategy that leverages the experimental system provided by C. elegans, with state-of-the-art molecular biology and genetics approaches. The strategy we have outlined will yield knowledge on the functions of these important regulators at the organismal and cellular level and will bridge that with a deep understanding of molecular mechanism based on our strong focus on identifying functionally critical targets. Knowledge of these targets has allowed us to begin to address how changes in their dosage, even if modest, affect cellular processes and ultimately development and physiology. Our findings in C. elegans are also guiding investigation of these conserved miRNAs in mammalian cell models. Our work will reveal the functions of essential, conserved miRNA genes and will uncover cellular pathways for which dosage control is important. We anticipate that this knowledge will be important to interpret mechanisms of human disease.

NSF Awards · FY 2025 · 2025-05

Concrete is the most widely used building material globally. Around 4.6 billion tons of cement is produced annually to meet growing urbanization, industrialization, and infrastructure demands. However, conventional Portland cement manufacturing is among the most energy intensive industries, primarily due to its high-temperature production process. This Future Manufacturing Seed Grant (FMSG) research project explores a novel, lower-energy approach to cement manufacturing by combining biological and chemical processes that will leverage waterways’ massive capacity to hold onto the key components used in cement production. Photosynthetic microbes called cyanobacteria look to be harnessed to produce solid calcium carbonate, a key component of cement, using sunlight and minerals in water. This microbially produced calcium carbonate plans to then be combined with sand and other materials for a promising alternative route to cement manufacturing. The success of the project will help enhance the competitiveness of US manufacturing and increase the availability of critically needed building materials, ultimately lowering the costs for production of new buildings for homeowners and businesses. The biomineralization of calcium carbonate from water sources using cyanobacteria is currently challenging for manufacturing applications. In this research project, the natural microbial carbonate mineralization process looks to be applied and improved through modification of the producer organisms and by controlling external environments to generate key components for biocement. Calcium carbonate production using microbes requires high carbonate concentrations in concert with elevated calcium levels and availability of chemical conditions that facilitate solid precipitation. Synechococcus elongatus cyanobacteria and other strains important to calcium carbonate formation look to be modified to enhance precipitation of calcium carbonate in the environment. Delivery of calcium carbonate seeks to be improved by increasing nucleation processes that facilitate carbonate precipitation to overcome barriers to solids formation. In concert, manipulation of extracellular conditions through electrochemical adjustment of environmental pH intends to ensure maximum conversion of reactants to calcium carbonate precipitate. Next, an integrated and scalable biocement manufacturing process that combines cyanobacterial growth and precipitation steps plans to be designed and implemented. A final goal will be to include biocement in infrastructure materials and test that these materials are mechanically stable and possess sufficient stiffness and strength. The project will include experts in microbial biomanufacturing, electrochemical engineering, and mechanical testing. Further, this project looks to train future engineers from high school to graduate levels in key concepts including microbial fermentation, electrochemistry, and mechanical testing of materials, and demonstrate how these skills will be applied to design, develop, and implement the next wave of innovative, low-cost manufacturing processes. 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 2026 · 2025-05

Project Summary/Abstract The overwhelming public health burden of HPV-associated head and neck cancer (HNC) has created great demand for novel, broadly effective therapies with reduced treatment morbidity and improved long- term survival. The generation of tumor-specific CD8+ T cell immunity requires potent antigen cross-presentation by dendritic cells (DCs) since tumor cells do not efficiently present relevant CD8+ T cell epitopes. Because of this, innovative strategies to enhance cDC1s could robustly induce HPV-specific immunity and have great therapeutic potential in the treatment of HPV-associated HNC. FMS-like tyrosine kinase 3 ligand (Flt3L) is a cytokine that expands and differentiates DC precursors to murine cDC1s. Furthermore, IFNβ is a type I interferons, a major class of immune cytokines, that can act directly on CD8+ T cells to increase cytotoxicity and survival by increasing the expression of cytotoxic T cell markers. However, therapeutic potential of Flt3L and IFNβ is limited because of their short half-life and global distribution in vivo. We have overcome the described issues by generating a genetic fusion of Albumin (Alb) to Flt3L, named Albumin-Flt3L (Alb-Flt3L), and the genetic fusion of Alb to IFNβ, named Albumin- IFNβ (Alb- IFNβ). Alb has a long half-life due to FcRn mediated transcytolic recycling. Once cDC1s expand, they require a strong, tissue localized source of inflammation for activation, or they will present T cell epitopes without adequate costimulation, causing suppression. Enteric bacteria such as Salmonella serve as an ideal agent for tumor specific cDC1 activation as they can provide numerous pathogen- associated molecular patterns for cDC1 activation, and have been described to colonize the tumor efficiently likely due to hypoxia. However, the use of heat-inactivated Salmonella results in weak immunogenicity and potency. Therefore, something that is more potent and can penetrate tissue without the safety concerns of using live bacteria is needed. We overcame this issue through the usage of Salmonella derived outer membrane vesicles, which is considered safer and can effectively stimulate the immune system by presenting key immunogens from their parent bacteria while also showing promise as a drug delivery agent. By coating SOMV with 9RE7 peptide, we produced a novel approach of SOMV-9RE7 that serves as a safer and more effective drug delivery agent. The combination of Alb-IFNβ, Alb-Flt3L, and SOMV-9RE7 capitalizes on the strengths of these approaches, offering a synergistic strategy and valuable preclinical data for cancer treatment by targeting multiple mechanisms and addressing cancer resistance in HPV-associated head and neck cancers. Specifically, we will: Aim 1: Evaluate and compare the ability of Sal-9RE7 and SOMV-9RE7 to mediate tumor control and induce HPV E7-specific T cell immunity. Aim 2: Evaluate the potency of the combination treatment of Alb-Flt3L + Alb-IFNβ + SOMV-9RE7 to mediate tumor control and induce HPV E7-specific T cell response. Aim 3: Characterize the mechanism of Alb-Flt3L + Alb-IFNβ + SOMV-9RE7 combination in mediating antitumor immunity.

NSF Awards · FY 2025 · 2025-05

This project addresses the critical issue of determining the best way to incentivize electricity producers to build sufficient power plant capacity to keep the electrical grid resilient, reliable and sustainable, all this while satisfying consumers. The goal is to provide regulators with tools to promote beneficial portfolios of battery storage and electricity production technologies, while also accounting for risks, transmission limitations and unpredictable events. Other outcomes of this project are expected to include development of new classes on Electricity Markets, support of new graduate students working in this area, and industrial collaborations. A recurring question in electric power markets has been: are spot prices sufficient to incentivize enough investment in generation capacity, storage, and demand-side management in order to ensure reliable and sustainable operating conditions? In other words, are spot prices enough by themselves to stimulate efficient mixes of electricity supply and storage that ensure that the resulting grid is resilient, reliable and sustainable? This question will be addressed by a new framework that will incorporate realistic market features and explore their implications for short- and long-run equilibria, optimal capacity prices, and net benefits of market designs. These features include battery storage and variable wind and solar resources, as well as risk-aversion, incomplete markets, transmission congestion, optimal demand management, and other features. The new framework will use a unique set of analytical and computational methods to solve for Nash equilibria in market models that are unique in their combining representations of stochastic demand processes, market participant risk attitudes, and simultaneous consideration of the role of regulators, market operators, suppliers, and consumers. The proposed framework can be simplified to have tractable dynamics, and also is general enough to incorporate all the desired features of real markets, including battery storage, variable renewables, transmission limits, evolution of capacities, and optimal demand management. The goal will then be to find Nash equilibria among the supply capacities of producers, together with the regulator's optimal capacity payments that maximize net market benefits. The aim is to compare energy-only and capacity markets, find the combination of capacity payments and price caps that maximize the reliability and net benefits of the market. In the near future, the demands upon the grid are expected to dramatically increase, as more applications switch from fossil-fuels to electricity (e.g., electric vehicles), and new uses appear (e.g., AI, bitcoin mining). Therefore, it is vital to study how to keep supply reliable and affordable, and desired generation facilities financially sustainable (in a Nash equilibrium sense), while achieving social goals of renewable power by providing incentives to the producers to "do the right thing." 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 2026 · 2025-05

Project Summary: Cell fate specification is generally considered to be a tightly controlled process, guided by lineage and signaling mechanisms that lead to reproducible outcomes. However, some cell fate decisions rely on stochastic mechanisms in which cells randomly choose between two or more fates with a set probability. Stochastic cell fate specification arises from inherent molecular noise in gene expression. Very little is known about how variability in gene expression drives fate decisions during metazoan development. This project will investigate stochastic cell fate decisions in the developing visual system of Drosophila melanogaster, which contains a stochastic, binary fate choice. The fly eye consists of a mosaic of two R7 photoreceptor subtypes that are defined by their expression of light-detecting Rhodopsin 3 (Rh3) or Rhodopsin 4 (Rh4) proteins. The choice to express Rh3 or Rh4 is controlled by a transcription factor called Spineless (Ss), which is randomly expressed in 67% of R7 photoreceptors (SsON R7s). ss is expressed in two distinct phases during eye development. The early and late expression of ss is regulated by two enhancers (the “early” enhancer and “late” enhancer). Early expression is noisy, with R7 precursor cells expressing ss at different levels. Interestingly, about 67% of precursors express ss at high levels while 33% express at low levels, which corresponds to the proportion of terminally differentiated SsON/ SsOFF R7s. Manipulating DNA elements (silencers and enhancers) and the transcriptional repressor Klu changes the level of early ss expression and the proportion of SsON/SsOFF R7s. From these data, I hypothesized that variable expression of ss early sets the ratio of SsON/SsOFF R7s late. Based on this model, I will investigate how regulation of transcription and chromatin dynamics produce variable ss expression to determine the stochastic R7 fate choice. Gene expression involves inherently noisy molecular processes, resulting in fluctuations in the amount of mRNA produced within a cell at a given time. Transcription is a major source of gene expression noise, occurring in bursts that differ in size, duration, and frequency. These bursts are strongly influenced by chromatin architecture and transcription factors. This work will use the MS2/MCP and DNA labeling lacO/LacI and parS/ParB systems to monitor and characterize ss transcription and chromatin in live developing cells (Aim 1 & 2). These experiments will establish the link between early ss transcription, chromatin dynamics, and terminal fate by monitoring endogenous expression and compaction from the precursor stage to terminal differentiation (Aim 2). Ultimately, this work will uncover generalizable mechanisms that regulate stochastic cell fate specification.