University Of Illinois At Chicago

NSF Awards · FY 2024 · 2024-06

In the digital age, the ability to identify anomalies quickly and accurately within massive datasets is critical for ensuring the safety, security, and efficiency of numerous sectors, including healthcare, national security, and finance. Anomalies, which represent deviations from the norm, can indicate critical issues such as potential security breaches, health crises, or financial fraud. The open tools and systems for anomaly detection (AD) are often fragmented, complex, and not easily accessible. This project aims to revolutionize this landscape by developing an integrated, open-source ecosystem that simplifies AD. By making advanced detection tools widely available and user-friendly, the OpenAD ecosystem will empower researchers, businesses, and public institutions to leverage the full potential of AD. This project seeks to unify existing AD systems into a comprehensive ecosystem that supports diverse data types and application domains. This ecosystem will integrate a wide range of open-source AD tools, including those for tabular, graph, and time-series data, and provide a platform for seamless integration of model evaluation, automation, and acceleration. The project's goals include developing a standardized development environment, enhancing tools for automating and accelerating detection processes, and establishing a governance structure to guide community contributions and project evolution. By leveraging the collective expertise of a diverse community of developers, researchers, and users, OpenAD aims to overcome current limitations in AD. The resulting ecosystem will not only facilitate more effective and efficient detection of anomalies across various domains but also foster innovation and collaboration within the scientific community. Through OpenAD, AD tools will be more accessible, powerful, and capable of addressing the complex challenges of the increasingly data-driven world. 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 · 2024-06

Project Summary Photoreceptor kinases are multi-domain signaling proteins that regulate a wide range of light responses in living organisms. They share similar modular protein architecture with many receptor kinases involved in virulence detection, and cell metabolism, migration, and differentiation. Despite their importance in signal transduction and disease biology, how receptor kinases couple a molecular trigger such as light absorption or ligand binding to a phosphorylation signal remains elusive at both the structural and mechanistic levels. The primary challenge is that these signaling proteins are intrinsically dynamic, largely limiting structural studies to their truncated forms. However, a complete mechanistic understanding requires structural and functional interrogation of full-length proteins in which both sensor and effector domains are present. To address these challenges, we will harness recent advances in cryo-EM single particle analysis to investigate the structures and dynamics of full-length photoreceptor kinases that share key mechanistic aspects with their prokaryotic and eukaryotic counterparts. Our long-term goal is to elucidate the general principles of signaling and allosteric regulation in modular receptor kinases by provoking and resolving functionally relevant structure dynamics. Building on our expertise in photoreceptor research, we will take an integrated approach of structural biology, biochemistry, and spectroscopy to tackle the molecular mechanisms of light-dependent kinase activation in two representative bilin-based photoreceptors - a canonical bacteriophytochrome and a dual-sensor photoreceptor kinase. Our supporting data have revealed light-induced global protein reorganizations in both systems, demonstrating the feasibility of these studies. In this project, we will first determine the full-length structures in different signaling states by resolving structural heterogeneity. We will then establish the functional relevance of the resolved structures by comparing their population change between datasets obtained under different light and ligand conditions. We will also dissect the motions in the central helical spine while addressing the roles of dimer asymmetry and order-disorder transition in long- range signaling via a joint analysis of conformational states captured by cryoEM and crystallography. Last but not the least, we will employ complementary methods of mutagenesis and functional assays to interrogate key interactions underlying the allosteric regulation and signal integration. Findings from the proposed studies will provide unprecedented insights into the molecular events driving the allosteric actions in modular receptor kinases beyond photoreceptors. Bilin-based photoreceptors are photo-switchable, spectrally versatile, and modular in function. They hold great promise in diverse biomedical applications exploiting light to probe cellular processes, modulate biological functions, and treat human diseases. Importantly, the mechanistic understanding gained from these naturally occurring photoreceptors will lay the foundation for ultimately engineering light-activated enzymes of desired signaling logic in novel therapeutic solutions via optogenetics.

NIH Research Projects · FY 2025 · 2024-06

Walking impairment is one of the most prevalent and life-altering consequences of multiple sclerosis (MS), even in the early stages of the disease, and often co-occurs with an increase in the oxygen (O2) cost of walking. The O2 cost of walking is the amount of O2 consumed per kilogram of body weight per unit distance traveled and reflects the physiologic strain or burden of ambulation. This physiological measure of walking dysfunction is 2-3 times higher in persons with MS than adults from the general population and compromises free-living, community participation. The higher O2 cost of walking further causes early onset of fatigue, hinders the performance of tasks necessary for daily living, and has been linearly associated with worse disability status in MS. This is noteworthy, as a primary determinant of disability status and progression in MS includes cardiovascular comorbidity. Of note, aerobic capacity, a primary indicator of cardiovascular function, has been identified as a strong correlate of O2 cost of walking in persons with MS who have moderate disability. Consequently, the logical next step in this line of research involves identifying potential physiological mechanisms that underlie elevated O2 cost of walking, and vascular function and peripheral blood flow represent the logical starting points based on associations with aerobic capacity and muscle function. Vasodilatory capacity of arteries is necessary for appropriate peripheral blood flow delivery and O2 extraction within the active muscle. Vascular function is typically assessed in the upper limbs (i.e., brachial artery), but vascular dysfunction of the upper limbs may not be indicative of vascular dysfunction of the lower limbs. This cross-sectional, comparative study will use non-invasive methods to compare vascular function (i.e., muscle blood flow and oxygenation) of the lower limbs (i.e., popliteal artery) between persons with MS and controls matched by age and sex, and then examine markers of vascular function as possible modifiable correlates of O2 cost of walking in MS. The first aim is to compare the O2 cost of walking and lower-limb muscle blood flow and oxygenation between persons with MS and controls. We hypothesize persons with MS will demonstrate higher O2 cost of walking and lower muscle blood flow and oxygenation in the gastrocnemius muscle compared with controls. The second aim is to examine the associations among the O2 cost of walking, lower- limb muscle blood flow and oxygenation, and aerobic capacity in persons with MS and controls, controlling for physical activity. We hypothesize that vascular outcomes, and secondarily aerobic capacity and physical activity, will account for the difference in the O2 cost of walking between groups. This research may identify specific underlying vascular mechanisms that explain the poor walking efficiency in MS and guide the design of targeted approaches for improving walking efficiency and its consequences to promote health and better overall quality of life. This research aligns with the PI’s research agenda of helping persons with neurological conditions reintegrate into the community post-diagnosis through improvements in walking efficiency.

NSF Awards · FY 2024 · 2024-06

The proposed project is a three-day conference aimed at recruiting, retaining, and supporting underrepresented biomedical engineering (BME) PhD students through postdoctoral studies, and into academic careers. The project is significant because there is a great need for a more diverse faculty pool in BME to continue to educate and inspire BME undergraduates, a group that is becoming larger and more diverse every year. In addition, diversity of BME faculty increases diversity among research projects, improving the field of biomedical engineering and seeking to assist in decreasing health disparities. A cohort of 25 diverse BME PhD students from all sexual orientations, racial and ethnic groups, socio-economic status and some who are first generation in their family college-bound, will be selected to participate, receive a $500 honorarium, and have their travel and lodging expenses reimbursed. They will learn about the pathways to becoming a BME faculty member and the opportunities they then will have to make an impact on education and research. They will learn about the tools needed to build a successful academic career in BME, and they will meet a diverse group of mentors and future collaborators, expanding their professional network. Over the past decade, biomedical engineering (BME) faculty nationwide have recognized significant attrition in graduating PhDs with an interest in careers in academia. This has manifested as fewer candidates for postdoctoral research associate positions, a critical period for the transition from student to independent scientist. The associated loss of postdoctoral researchers' talent greatly threatens the vitality of our research workforce in the US and our nation’s ability to broaden the representation of faculty from all sexual orientations, racial and ethnic groups, socio-economic and first generation to college status, and religions. There has been a significant loss of talent within the mid region of the U.S. despite it being a haven for biomedical industry partnerships and startups begun by BME faculty. Initial discussions revealed that BME graduates in the Midwest did not believe it possible to identify career-building post-graduate research opportunities without uprooting partners and families or moving away from their deep community connections. Thus, in June 2022, seven universities across the Midwest region came together to host the inaugural 2022 Rising BME Scholars Regional Career Conference at Washington University, and a second one in 2023 at the University of Minnesota. The goal of this regional conference is to “inspire, strengthen and diversify the next generation of academic researchers in BME” by encouraging underrepresented Ph.D. students and providing them with the practical skills and confidence needed to apply and succeed in academia. In 2024 we propose to offer a new version of the conference at the University of Illinois Chicago (UIC), with significant modifications based on feedback from the first two events. Per previous participant feedback, new topics will include alternative career paths for BME faculty in academia, such as focusing on teaching and education research, as well as work/life balance. RSC participants will also learn from BME faculty from UIC and the eight other sponsoring institutions about opportunities to engage in research and education to decrease health disparities. Looking forward, we expect to have a critical mass of prior participants we can survey annually to get their perspective on the conference’s impact and their current career trajectory. We anticipate this conference will not only positively impact its participants, but through follow-up surveys will help us identify programming and strategies that have the lasting impact. The UIC environment is well-suited for this conference as it is among the nation’s top ten most diverse campuses and is designated a Minority Serving Institution (MSI) and Hispanic Serving Institution (HSI). 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 · 2024-05

The ovarian hormone estrogen promotes binge drinking and contributes to sex differences in alcohol abuse. Interestingly, we found an association between estrogen signaling and the brain serotonin (5-hydroxytryptamine, 5-HT) system, a key modulator of alcohol intake. For example, both estrogen receptor α (ERα) and β (ERβ) are highly expressed in the 5-HT neurons in the dorsal raphe (5-HTDRN), the largest serotonergic neural population and a major source of 5-HT. Notably, chronic binge-like ethanol intake led to sex-specific alterations in mRNA expression of ERα and 5-HT-related genes in the DRN in mice, suggesting a potential role of estrogen/ERs/5- HT signaling in binge drinking. Notably, we found that either ERα or ERβ agonist treatment attenuated the stimulatory effects of alcohol on 5-HTDRN neurons, which may contribute to the higher levels of binge drinking in females. We also showed that chemogenetic activation of ERαDRN or ERβDRN neurons reduced binge drinking in female mice. These results support a model in which estrogen acts on ERα/β to prevent alcohol-induced activation on 5-HTDRN neurons, leading to higher binge alcohol drinking. To test this hypothesis, we will pursue three aims in the current grant. (1) We will test whether ERα and ERβ expressed by 5-HTDRN neurons are required for estrogenic regulation of alcohol binge drinking. (2) We will determine whether estrogen signaling mediates the sex dimorphic response of 5-HTDRN neurons to alcohol excitation. (3) We will determine the 5-HTDRN downstream neural circuit that mediate the stimulatory effects of estrogens on alcohol binge drinking. Thus, the proposed studies will be able to identify the specific receptor, neural population, neuronal firing, and neural circuit mechanisms that mediate estrogens’ stimulatory effects on binge drinking. This proposal will investigate one of the fundamental mechanisms contributing to the sex-dimorphism of excessive drinking. The results will provide novel information for identifying new targets to develop more effective, individualized treatment for binge drinking and alcohol-use disorders.

NIH Research Projects · FY 2025 · 2024-05

ABSTRACT The nicotinic acetylcholine receptors (nAChRs) have been implicated in a variety of central nervous system (CNS) disorders. However, the significant similarity between subtypes has limited the discovery of subtype- selective nAChR antagonists. As a result, the pharmacological utility of the nAChRs depends on the development of improved ligands. Recently, several alkaloids isolated from Aristotelia chilensis were identified as nAChR antagonists that preferentially antagonize the α3β4 subtype over the α4β2 and α7 subtypes. While other α3β4 antagonists exist, they also have poor pharmacokinetic properties and multiple off-target liabilities, making the subtype-selectivity the Aristotelia alkaloids possess particularly unique. In addition, preliminary competitive studies indicate that these alkaloids act through an allosteric mechanism of action, in contrast to other antagonists that are largely orthosteric ligands or channel blockers. Previous studies of the Aristotelia genus have identified >30 unique alkaloids, but few studies have been conducted on their biological activity. My central hypothesis is that these understudied Aristotelia alkaloids are also subtype-selective nAChR antagonists that operate through an allosteric mechanism of action. To investigate this, in Aim 1, I will extract alkaloids from the leaves of A. chilensis through a novel countercurrent chromatography approach, isolating known natural products while also potentially discovering novel alkaloids. In a complementary approach, Aim 2 seeks to access known Aristotelia alkaloids via a series of biomimetic transformations. Armed with a library of alkaloids, Aim 3 will evaluate their activity at multiple nAChRs through a functional assay. Competitive inhibition studies will be done to investigate the potential allosteric mechanism of action, while mutagenetic analysis will identify which residues on the receptors are crucial for activity and reveal differences between subtypes. While making synthetic advancements, this research is both innovative and significant as it will be the most extensive biological evaluation of the Aristotelia alkaloids to date, providing tools to probe the nAChRs as a whole, as the alkaloids establish an entire class of subtype-selective nAChR ligands.

NIH Research Projects · FY 2026 · 2024-05

SUMMARY Studies have demonstrated an increased risk of aggressive prostate cancer (PCa) with vitamin D deficiency. Mounting evidence from my lab demonstrates that vitamin D deficiency alters the hormone levels of the prostate, which may contribute to the increased risk of aggressive PCa in vitamin D-deficient men. Our recent publications and preliminary data show that vitamin D status regulates dihydrotestosterone levels in the prostate, providing a mechanism by which vitamin D affects PCa aggressiveness. We further implicate megalin as mediating the effect of vitamin D on prostate androgens. Our long-term goal is to thoroughly examine the relationship between vitamin D and androgen hormones systemically. Here, we propose to examine megalin as a critical protein involved in prostate hormone regulation. The project includes three complementary, yet independent aims and the approach combines analysis of patient-derived models and mouse studies with clinical samples. This proposal aims to test the hypothesis that vitamin D deficiency leads to increased prostatic androgens via megalin, resulting in an increased risk of aggressive PCa. In contrast to serum levels, there is a paucity of information regarding the regulation of intra-tissue levels of hormones. Given that megalin regulates prostate T levels AND that megalin is regulated by vitamin D, further understanding this mechanism will provide crucial new insight into the consequences of vitamin D deficiency. New insight that directly links vitamin D status to prostate androgens has the potential to move the needle for general practitioners who would then take vitamin D deficiency seriously. Our findings may lead to increased screening for and treatment of vitamin D deficiency, ultimately decreasing the burden of aggressive and lethal PCa.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract As the most common neurodegenerative disease of dementia, Alzheimer’s disease (AD) causes progressive memory loss and cognitive impairment. AD has neither a clear pathogenesis nor effective treatments. Its progression is marked by loss of neurons at the time of diagnosis. The proximal causes of this loss are not well understood. Nevertheless, neuronal loss follows loss of synapses, and earlier loss of synaptic function is a leading aspect of the disease. My goals are to gain expertise in modern principles and understanding of AD and animal models of AD from lectures, from access to our graduate training program in AD research and from my highly skilled mentoring team. I will use those skills to aid my research into the role of the synapse in AD. Based on preliminary data that loss of synaptic function in humanized APOE4 mouse models at excitatory synapses in the hippocampus, I propose that a critical factor in synaptic transmission is presynaptic Ca2+ signaling and homeostasis. Amongst, the first brain regions to be affected in AD patients is the hippocampus, a critical brain area for cognition and memory and we and others have observed APOE subtype dependent changes in evoked plasticity in hippocampal synaptic transmission. I propose to use high spatiotemporal resolution approaches to imaging synaptic transmission and presynaptic signal transduction. However, dynamic imaging of these events means that continuous irradiation causes photodamage and phototoxicity. For my research program and to overcome this problem, I have used my physics background to build a light sheet instrument, called lattice light-sheet (LLS) using the approach developed by Eric Betzig 1, that uses a linearly polarized sheet of light with a binary phase map of Bessel beams to form optical lattices which markedly increases the axial resolution to ~400 nm. It allows extremely fast image acquisition (up to 1 KHz frame rates) and minimal phototoxicity. Using the LLS microscope, I can resolve fast components of synaptic transmission, including neurotransmitter release. I have also developed a novel approach for LLS imaging of incoherent holography to scan the sample volume without moving the detection objective. This enables an increase in axial resolution and allows me to visualize intact neural tissue, with access to quantitative information of samples being imaged. Using the training possible through this K25 program I will now interrogate synaptic dysfunction in presynaptic terminals for its role in neurogenerative disorders, such as Alzheimer disease. I will combine my imaging expertise and resources that I have built in the Alford laboratory with the expertise and availability of mouse models of neurodegeneration available from my mentors, Drs Tai and Lazarov along with circuit expertise in the Tseng laboratory to understand loss of synaptic function associated with neurodegenerative disease. This provides the foundation for my training, adding to my expertise as an accomplished physicist and imaging specialist who wishes to apply these skills to understanding the aging brain.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY / ABSTRACT Cerebral palsy (CP), the most common cause of childhood disability, results from a non-progressive disturbance to the developing brain and leads to impairments which negatively impact mobility and function. Individuals with CP demonstrate abnormal reactions to anticipated (proactive) and unanticipated (reactive) balance challenges, placing them at increased risk of falls. Adults with CP are 3.64x more likely to fall than their typically developing peers, and the incidence of falls in children with CP is similarly increased. Balance control is worsened with the addition of a secondary (dual) cognitive task. This causes cognitive-motor interference, which results when motor and cognitive tasks are competing for the same resources and leads to degradation in performance of one or both tasks. These cognitive-motor tasks mimic daily life situations such as walking and talking with friends, and the difficulty that children with CP experience in these situations leads to declines in participation and function. Previous work has investigated this cognitive-motor dual task paradigm; however, all studies have utilized proactive balance challenges, with the primary motor tasks of balance or straight path ambulation. Evaluation of a more functional proactive balance task, such as obstacle negotiation, is needed in the context of a cognitive-motor dual task situation. Additionally, previous studies have shown that children with CP fall more and have decreased stability during single task reactive balance challenges; however, this single task condition requires the addition of a secondary task to become functionally relevant and mimic daily life scenarios. Our specific aims will address these mechanistic and participatory gaps in the literature by investigating: (1) proactive balance control through negotiation of an overground obstacle in single and dual task conditions, in children with CP compared to TDC; (2) reactive balance control through stance slip-like treadmill induced perturbations in single and dual task, in children with CP compared to TDC; and (3) the correlation between balance control and participation in mobility-related habits of daily life in children with CP utilizing the LIFE-H, linking the biomechanical and mechanistic laboratory findings (Aims 1 +2) to participation and quality of life (Aim 3) for children with CP. We hypothesize that children with CP will demonstrate decreased stability and greater falls in both single and dual task conditions when compared to TDC, and that both groups will experience these declines in performance, when compared to themselves, in dual task conditions. The results from this study will be integral in establishing the mechanisms underlying balance control during functional proactive and reactive balance challenges, and how this stability correlates with overall mobility-based participation for children with CP. This will provide valuable insights for developing effective clinical interventions and improving the quality of life and participation of children with CP. The findings will contribute to the design of future research paradigms and facilitate the translation of intervention strategies into clinical practice.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY This application proposes a customized research training plan designed to promote the development of the applicant into an independent investigator. The plan includes advanced training in laboratory experimentation, along with tailored professional and career development opportunities. The training plan is supported by the outstanding availability of local and institutional resources at UIC. The proposed research will investigate the role of extracellular vesicles in mediating endothelial cell-fibroblast communication in the healing wound. In human skin, the process of wound repair involves angiogenesis, which includes the creation and then pruning of vessels. Simultaneously, fibroblasts in the wound are responsible for the deposition of the extracellular matrix components that surround the new vasculature. The goal of the proposed studies is to examine how endothelial cells communicate with surrounding fibroblasts in the wound. Several previous studies demonstrate that these two cell types may utilize paracrine methods of communication to influence or enhance their functional roles, but how this intercellular interaction occurs is largely unknown. One potential mechanism by which endothelial cells might communicate with fibroblasts is through extracellular vesicles and their microRNA cargo. Recent studies in our lab have shown that fibroblasts treated with extracellular vesicles from endothelial cells exhibit significant transcriptomic changes. Based on this preliminary data, our central hypothesis is that in the healing wound, endothelial cells secrete extracellular vesicles that influence the function of resident fibroblasts. The research plan utilizes methods for extracellular vesicle purification and application, traditional in vitro and in vivo wound healing assays, and advanced bioinformatics techniques to study extracellular vesicle-mediated communication between these two cells types. Aim 1 will determine how fibroblast phenotypes are altered by endothelial cell extracellular vesicle treatment, and will examine the role of cargo microRNAs in the observed changes. In vitro studies will elucidate the effect of endothelial cell extracellular vesicle treatment on the fibroblast transcriptome and key fibroblast functions, such as collagen contraction, deposition, and proliferation. Aim 2 will evaluate how endothelial cell extracellular vesicles affect fibroblast phenotypes in the wound in vivo using a splinted murine skin wound model. The effect of extracellular vesicle treatment will be examined for multiple parameters of healing, including collagen content and architecture, myofibroblast activation, angiogenesis, and wound closure. Finally, single cell-RNA sequencing of wound fibroblasts will be used to determine how endothelial cell extracellular vesicle uptake modifies the fibroblast transcriptional profile. Together, the aims will lead to a better understanding of the mechanisms by which endothelial cells might modulate fibroblast function, and may lead to the development of novel therapies to treat wounds or various skin and fibrotic diseases.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Gaps and misconceptions in patient knowledge can contribute to poor care adherence, decreased quality of life, and even negative outcomes, especially in underserved populations. There is an urgent need to systematically capture, characterize, and develop mechanisms for breast cancer patient knowledge sharing. The objective of the proposed feasibility and acceptability pilot study is to capture lived experiences of breast cancer patients and characterize their knowledge types, levels, and gaps longitudinally. Topics include comprehension of illness (type, stage, prognosis), treatment decision making, navigating emergent events resulting in deviations from treatment trajectory (e.g. hospitalization for neutropenic fever). In a collaboration between human factors researcher, medical oncologist, and a patient partner, we will conduct semi-structured Cognitive Task Analysis interviews to elicit breast cancer patient experiences longitudinally (prior to first treatment, 6 months and 1 year after diagnosis). We recruit ~35 adult breast cancer patients. We will analyze interview data using thematic analysis and develop taxonomy of patient knowledge across the care continuum. The expected impact is: 1) understanding patient knowledge and gaps as a function of time/experience and 2) gaining insight into designing human-centered and culturally sensitive patient education.

NIH Research Projects · FY 2026 · 2024-04

Project Summary/Abstract The overall goal of this proposed Mentored Patient-Oriented Research Career Development Award (K23) is for the candidate, Dr. Sarah Messmer, to become an independent investigator in implementation science and substance use disorder treatment, with a focus on opioid use disorder treatment in low-barrier and community- based settings. Given that opioid overdose deaths have reached an all-time high in the United States, the development and implementation of evidence-based interventions to treat opioid use disorder is critical. To become an independent investigator in this area, the candidate requires additional formal training in the following areas: 1) implementation science in substance use disorder research; 2) clinical trials design; and 3) ethical considerations in substance use disorder research. The candidate’s mentorship team includes Dr. Niranjan Karnik, Dr. Sara Becker, Dr. Dennis Watson, and Dr. Rachel Caskey, who will support the candidate in the proposed training and research plan. The overall objective of the proposed research is to implement an adapted contingency management program within a mobile lowthreshold buprenorphine program. Contingency management is one of the most effective behavioral health treatments for substance use disorder, including when provided concurrently with medication for opioid use disorder. However, implementation barriers have limited its use, particularly in community-based settings. This proposal seeks to engage stakeholders to identify implementation barriers and develop targeted implementation strategies that can be utilized for contingency management programs within community-based, low-barrier settings, with a primary goal of increasing retention in care for patients with opioid use disorder. The proposal will be guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) implementation framework, with the ADAPT process model embedded to guide the stages of adaptation. In Aim 1, the candidate will complete focus groups and interviews with a group of stakeholders including people who use drugs, community-based programs, policymakers, researchers, and substance use treatment providers to identify barriers and facilitators for the intervention. In Aim 2, the candidate will work with an adaptation team of key stakeholders to adapt a contingency management program and develop an implementation plan for use in a low-barrier mobile setting. In Aim 3, the candidate will conduct a 12-week pilot study of the adapted contingency management program and corresponding implementation strategies with patients with opioid use disorder engaged in low- threshold treatment via mobile van. The outcomes of this study will provide the foundation for an R01 proposal for a larger clinical trial of the adapted intervention. This award would provide Dr. Messmer with the mentorship, training, and research experience to become an independent investigator in implementation science and substance use disorder treatment focused on community-based low-barrier care models.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Staphylococcus aureus asymptomatically colonizes 30% of the human population. However, the bacterium can breach innate host defenses to gain access to deeper tissues and vasculature allowing it to infect diverse tissue sites such as the heart, lungs, blood, bones, and skin. Despite distinct nutritional limitations at these sites, we know comparatively little about how S. aureus adapts its metabolism to survive and cause infection. To better combat infections caused by S. aureus, it is imperative to understand how the bacterium changes metabolic flux to adapt to nutritional restrictions imposed by host tissues. Several metabolic enzyme complexes involved in S. aureus central metabolism are activated via the covalent linkage of the cofactor lipoic acid to E2 subunits. The transfer of lipoic acid to E2 subunits is mediated by the amidotransferase, LipL. Notably, LipL transfers lipoic acid to a critical enzyme used in glycolysis, pyruvate dehydrogenase. Pyruvate dehydrogenase use pyruvate to generate acetyl-CoA, a molecule that is crucial for several downstream metabolic pathways. Our prior studies and preliminary data established that LipL is genetically and functionally coupled to the phosphotransacetylase, Pta. Pta catalyzes the generation of acetyl-phosphate from pyruvate dehydrogenase-derived acetyl-CoA. Acetyl- phosphate is subsequently delivered to acetate kinase, AckA, to generate ATP during overflow metabolism. We recently demonstrated a potential interaction between Pta and LipL and found that a ∆lipL mutant produces negligible acetate in culture. Furthermore, the loss of either the pta or lipL gene results in significant attenuation in the host. Thus, we hypothesize that a functional link is established between Pta and LipL that enhances glycolytic flux by coupling pyruvate dehydrogenase activity (lipoylation) to acetogenesis (Pta-AckA) to promote energy balance and survival during infection (Aim 1). Additionally, we found that acetate production still occurs in a ∆pta mutant, suggesting compensatory enzymes - such as the pyruvate oxidase CidC - could be promoting acetogenesis and might affect virulence. Furthermore, we found that expression of lipL under the control of high and low expressing promoters regulated the transition from acetogenesis to TCA cycle activity. These results led us to hypothesize that LipL levels/activity establish a metabolite signature that controls (i) acetogenesis via CidC and (ii) TCA cycle activity to promote energy balance and S. aureus survival during infection (Aim 2). In Aim 1, we will determine how LipL interfaces with Pta to control energy balance during overflow metabolism. In Aim 2, we will investigate how LipL governs metabolic flux through CidC and the TCA cycle. Together, these Aims will lead to a better understanding of how LipL promotes metabolism, energy balance, and virulence in Sa.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT This application proposes a tailored research training plan that is designed to promote my development into an independent clinician-scientist. The plan includes a rigorous laboratory training experience in multiple techniques as well as a customized professional and career development plan. Furthermore, the training plan is supported by outstanding institutional resources, including a strong and interwoven research community and a supportive mentorship team. My research area of interest is translationally-relevant biomimetic approaches to tissue repair. In the field of tissue engineering, there is a need for therapeutic tools that target specific inflammatory and regenerative pathways. The NLRP3 inflammasome pathway is activated in several systemic diseases, such as type I and type II diabetes. This pathway also contributes to chronic inflammation and directly impairs repair and regeneration of various tissues within the body including bone and craniofacial tissues. Diabetes-related chronic inflammation and poor craniofacial bone repair are significant oral healthcare problems. Mesenchymal stem cell-derived extracellular vesicles (MSC EVs) and their miRNA cargo have high therapeutic potential for immunomodulation in dental diseases and craniofacial tissue regeneration. Several miRNAs within MSC EV cargo have been identified to regulate and suppress the NLRP3 pathway. However, there is a gap in knowledge regarding the lack of mechanistic approaches to direct pathway-specific manipulation of inflammation using EVs and to achieve controlled release of EVs to employ their therapeutic effects. The proposed research will address this gap in knowledge through developing a controlled release system for engineered anti-inflammatory EVs at wound sites. This release system will use an alginate-based hydrogel platform to deliver engineered EVs. The alginate-based hydrogel can be functionally modified by incorporating cell/EV binding motifs to the alginate backbone. The results of this proposal will work towards the long-term goal of maximizing the therapeutic potential of EVs and enhancing tissue repair. Aim 1 will utilize miRNA-based EV engineering to generate engineered MSC EVs to target the NLRP3 inflammasome pathway using miRNA-22-3p as the candidate. Aim 2 entails developing a photocrosslinkable hydrogel for the controlled release of engineered EVs using tissue resident metalloproteases abundant at wound sites as a trigger for EV release. Aim 3 is focused on assessing the efficacy of the engineered EVs and the delivery system in vivo using a diabetic mouse calvarial defect model. Overall, successful completion of these aims will provide me with a comprehensive training in EV biology and related techniques, stem cell biology, molecular biology, immunology, biomaterial design, imaging, animal handling and related histology and immunohistochemical techniques. Results from this work will directly address oral healthcare issues such as diabetes-related chronic inflammation and poor craniofacial bone repair.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Hepatocytes exhibit compartmental (zonated) functions along the sinusoid with as many as 50% of liver genes thought to be zonated. The initiation and progression of several diseases can show a zonated bias including drug-induced liver injury, non-alcoholic fatty liver disease, and hepatocellular carcinoma. The fetal liver is not zonated and thus zonation begins after birth due to gradients of O2, hormones, nutritional stimuli, and non- parenchymal cell (NPC) secretions acting on common pathways. As complementary tools to live animal studies, in vitro hepatocyte +/- NPC cultures subjected to specific factor gradients within fluidic devices can enable a more detailed understanding of the regulators and functional outcomes of zonation. However, previous in vitro platforms/studies have only been able to recapitulate limited features and an incomplete understanding of hepatic zonation. We have pioneered a droplet microfluidics platform for the high-throughput generation of reproducibly-sized 3D extracellular matrix (ECM) microgels (<300 µm) containing primary hepatocytes that display liver functions for 4+ weeks in vitro when the microgels are coated with primary liver sinusoidal endothelial cells (LSECs); microtissues can be further augmented with hepatic stellate cells (HSCs) and Kupffer cells (KCs). We have also developed microfluidic devices that enable precise microscale and spatial control over the O2 environment of cells with higher resolution than afforded for by conventional devices; such devices also uniquely allow decoupling of the effects of O2 from other soluble factor gradients that are typically induced via perfusion. Additionally, our data shows that primary rat and human hepatocytes display differential regulation of phenotypic functions when subjected to in vivo-like O2 tensions over prolonged culture. Here, we will test our novel hypothesis that microtissues can be used within custom microfluidic platforms to elucidate the roles of different soluble factor gradients, individually and in controlled combinations, on the long-term phenotypic responses of multiple liver cell types from rats and humans. In aims 1 and 2, we will elucidate the effects of physiological O2 tensions and the effects of hormonal and nutrient gradients on the long-term functions of rat and human liver microtissues, respectively. Lastly, in aim 3, we will utilize microfluidic devices that enable multiple overlapping soluble factor gradients to elucidate the effects of gradient crosstalk on multicellular zonation in rat and human liver microtissues. The detailed investigations here will be the first-of-their kind and will significantly increase our understanding of how key factor gradients and heterotypic cell-cell signaling affects liver zonation across human and rodents, which can be useful for building physiologically-relevant liver tissues for drug development across its various phases and ultimately regenerative medicine. Lastly, the microfluidic tools developed here can serve as a community resource to probe molecular mechanisms underlying liver zonation and how it affects the initiation and progression of several liver diseases and chemical-induced liver injury.

NIH Research Projects · FY 2026 · 2024-04

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Fetal liver hematopoietic stem cells (HSCs) are capable of rapid proliferation, robust functionality, and enhanced engraftment when used in a transplant setting. However, the complicated origins and migratory development of fetal HSCs have made their study difficult. It is not known why, and it has recently been debated if, fetal HSCs are superior to adult bone marrow HSCs. In previous studies, we have investigated the role of Notch signaling during fetal development where we have discovered a requirement for Notch1 in the viability and function of HSCs in the fetal liver (FL). We have also recently shown that the Notch ligand Jag1, expressed on hematopoietic cells, is required for function of FL HSCs. In this proposal, we will build on these findings to determine the mechanistic role of Notch signaling during expansion of fetal HSCs and how the fetal liver microenvironment sustains the growth, promotes the maturation and drives the functionality of definitive HSCs. Our preliminary findings indicate that multiple Notch receptors are expressed on FL HSCs and that Notch active cells are robust in engraftment and reconstitution after transplant. In Aim 1 we will leverage our discovery on reporter-based Notch activity to identify a sub-set of FL HSCs with enhanced functional potential. We hypothesize that Notch1 and Notch2 are active in the fetal liver, but that Notch1 activity is required for robust FL HSC activity. We will use in vivo transgenic animal models to conditionally delete Jag1 from specific fetal progenitors, myeloid and megakaryocytic cell types and will test functionality and visualize the FL niche that generates the most robust HSCs. Then, in Aim 2 we will extend our studies to identify novel factors that promote FL HSC expansion. We hypothesize that an antimicrobial family of secreted proteins are novel direct Notch target in FL HSCs, and that these cathelicidin peptides promotes FL HSC expansion. We will test this hypothesis by conditional transgenic deletion of novel target genes in hematopoietic cells and by supplementing the peptides in treatment of fetal, adult, and aged bone marrow HSCs. The knowledge gained from these aims will enhance our understanding of how microenvironmental signaling pathways during embryonic development drive stem cell expansion and function.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Drug tolerant cells limit clinical success of many types of anticancer therapies. Drug tolerance has largely been associated with cell heterogeneity. Surprisingly, identifying successful drug combinations has rarely been done at the cell population level. We propose that the limited success of therapeutic strategies is due to the gap in knowledge of the vulnerabilities of different cancer cell populations. We and others recently showed that during the initial response to cancer therapy, drug tolerant cells exhibit differences in gene expression across distinct cell subpopulations. The analysis of transcriptional phenotypes in lung cancer cell lines and xenografts treated with a single agent has guided us to a successful targeting of the drug tolerant populations with the second agent. This suggested to us that describing different cell populations using single-cell RNA data may be used for identifying scorable drug response signatures. We put forward an innovative idea of assessing druggable modulation in gene expression at the cell population level for identification of potential drug combinations. The goal is to find the drugs, each targeting distinct cell population/s tolerant to the first drug, to eliminate all cells with the prescribed combination treatment. This idea will be tested in three Specific Aims, by drug scoring based on cell population signatures, drug validation in cell survival assays, and drug validation through the characterization of affected cell populations. The data from single-cell RNA sequencing will be used for in silico drug prescription, and the top drug combinations will be validated in vivo for inhibiting growth of predicted cell subpopulations. To enhance translational value of this idea, we study the cell subpopulations that are tolerant to the treatment with standard-of-care cancer therapies; we use relevant cancer cell line models; and we determine applicability of our idea using large pan-cancer cohorts with available RNA-seq data. No drugs that target cancer cell heterogeneity have yet reached the clinic. However, the inhibitors available in the databases that we use, with known safety profiles, have been approved or are in clinical trials for cancer treatment, and they could be candidates for halting drug tolerance. The proposed research helps find new solutions and approaches for cancer treatment. It may enable oncologists to accurately tailor cancer care for individual patients with the drugs that target emerging tolerant cell populations. Patients stratified by markers predictive of drug response can enter clinical trials for combination therapy.

NIH Research Projects · FY 2025 · 2024-03

ABSTRACT Ninety percent of pregnant U.S. women have simultaneously over 50 different chemicals in their bodies. With over 70,000 chemicals registered with the U.S. Environmental Protection Agency and with many of which not yet evaluated for reproductive toxicity, understanding the effects of chemical exposure on placental function is much warranted. This is significant as many of these chemicals have the potential to alter placental function and the health of the placenta is critical to a healthy pregnancy as well as fetal and maternal well-being. However, studying the effects of chemical exposure on human placental function in vivo is filled with challenges, including ethical concerns, inadequacy of animal models to recapitulate human trophoblast cell invasion, and difficulty of working with limited primary cells that cannot be passaged many times. To advance the field of placental toxicology, suitable in vitro human models capable of mimicking in vivo conditions and enabling dynamic drug delivery in higher-throughput screening formats are urgently needed. Key limitations of available models include low throughput and chemical hepatic biotransformation that occurs in vivo. In this proposal, we plan to develop a high throughput system to test placental cell invasion using a 3D placental microtissue coupled with hepatic liver biotransformation. This first-of-its-kind hepatic-placenta organ-tandem on a chip will simulate the liver metabolism that chemicals undergo in vivo prior to reaching the placental bed. This state-of-the-art in vitro platform will be the first step towards incorporating organism-level organization into reproductive risk assessment using a non-animal-based approach. We anticipate that this new platform will be a key tool to be incorporated in the development of adverse outcome pathways for future placental risk assessment.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT: Hidradenitis suppurativa (HS), which affects approximately 6 million people in the United States, is a debilitating chronic inflammatory disease of the skin and subcutaneous tissue. HS presents as painful abscesses, boils, nodules, and fistulous tracts and patients with HS had the highest morbidity of all skin diseases. Treatment plans can average 14 years with patients trying multiple options to find relief. Even excisional surgeries have a high recurrence rate. Currently, clinical assessments of HS are accomplished through visual inspection and palpation, which underestimate disease stage and severity. Histological analysis identifies changes in vascularization, emerging fluid buildups, emerging tunnels, and structural changes in collagen, keratin and lipids not visible by clinical inspection. Ultrasound (US) imaging can aid in HS diagnosis and staging, but is infrequently used in the United States and is limited to detection of structural defects. Using optical excitation and acoustic detection, photoacoustic (PA) imaging has the capability to detect many biomarkers of HS identified by histology and could aid in HS diagnosis and treatment planning. The PI, an expert on PA imaging, has led a number of observational trials involving human imaging and has gathered input from dermatologists, pathologists, radiologists and HS surgeons on desired specifications for an HS imaging system. Here, he has assembled a strong team which has the background, experience and expertise to design, develop and test a portable PA/US imaging system with an easy-to-use hand-held probe for HS. The system, which will collect and analyze PA/US 3D volumes of an entire skin section, will include an algorithm that will automatically generate an HS likelihood map that calculates probability of HS involvement voxel-by-voxel across an entire imaging area. This goal will be accomplished through three Specific Aims: 1) Development of a 3D PA/US system with a hand-held probe to create volumetric data from HS lesions. The system and all components will be designed, optimized, and tested. 2) Identify and validate HS-specific PA biomarkers and use them to generate HS likelihood maps. We will collect PA/US data from subjects with HS and quantify biomarkers associated with HS. The biomarkers will then be used to generate a likelihood map, whose accuracy will be validated using healthy controls and histology data. 3) Demonstrate capability of 3D PA/US for (a) planning excisional surgeries by comparing PA proposed surgical volumes with 3D projections of the surgeon’s photographed surgical outline and (b) analyzing effectiveness of pharmaceutical treatments by comparing likelihood scores with clinical scores of treatment response. Impact. HS is typically assessed by visual inspection, palpation, and patient history. The proposed PA/US imaging system and associated HS-detection algorithm (the likelihood map) not only holds promise for reducing HS morbidity in direct clinical use by enabling more accurate surgeries and better-targeted pharmacological treatments, but will also assist future HS investigators to develop more effective drugs and individualized therapeutic strategies.

NIH Research Projects · FY 2026 · 2024-03

PROJECT ABSTRACT: Hepatocellular carcinoma (HCC) is an aggressive malignancy representing the 7th most common cancer globally and the 4th most common cause of cancer death worldwide. Although magnetic resonance imaging (MRI) represents a common HCC diagnostic and prognostic tool, MRI fails to provide insights into HCC risk stratification, and does not allow for rational therapeutic allocation. Chemical exchange saturation transfer (CEST) molecular MRI, on the other hand, permits noninvasive measurement of tumor metabolism predictive of malignancy. Integration of CEST MRI into clinical HCC management has the potential to radically alter clinical practice paradigms through: (1) identification of small malignant nodules and those with unconventional enhancement features to increase diagnostic performance; (2) improved prediction of tumor aggressiveness to inform patient prognosis and treatment stratification; and (3) monitoring of tumor metabolism in patients post therapy to differentiate between pseudoprogression—characterized by tumor regression following an initial increase in tumor burden—and true tumor progression. This proposal employs the innovative Oncopig Cancer Model—a transgenic porcine model that recapitulates human cancer through induced KRASG12D and TP53R167H expression—to test the hypothesis that noninvasive mapping of in vivo creatine (Cr) metabolism empowers prediction of differential HCC tumor aggressiveness. Combining our innovative Oncopig Cancer Model with MRI and CRISPR protocols optimized under our previously funded R03 and R21 grants, we will image Oncopig HCC tumors engineered to display differential Cr metabolism and malignant potential to demonstrate that Cr CEST MRI can accurately differentiate: 1) HCC malignancy due to intertumor genetic heterogeneity, 2) intratumor heterogeneity, and 3) pseudoprogression from true tumor progression. Genes targeted will include the ubiquitous mitochondrial Cr kinase (CKMT1), which converts ATP and Cr to ADP and phosphocreatine to meet cellular energy demands. CKMT1 knockdown reduces human HCC proliferation and migration in vitro, while increased CKMT1 serum levels are associated with poor prognosis following radiofrequency ablation. We plan to test our hypothesis by pursuing the following specific aims: (1) Demonstrate applicability of Cr CEST MRI for stratifying HCC malignancy reflective of intertumor genetic heterogeneity. (2) Demonstrate applicability of Cr CEST MRI for assessment of intratumor heterogeneity. (3) Demonstrate applicability of Cr CEST MRI to differentiate between pseudoprogression and true tumor progression. Oncopig HCC tumor growth and Cr levels will be quantified using a respiratory gated liver CEST MRI protocol to reduce motion artifacts. MRI-guided biopsy collection will enable co-registration—based comparison of in vitro measurements with Cr CEST for assessment of Cr CEST sensitivity and specificity. This proposal will radically alter HCC clinical practice paradigms by enabling noninvasive high-resolution in vivo molecular profiling to improve HCC diagnostic performance, treatment stratification, and treatment response monitoring.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Pregnancy is a critical period for brain development, and drug use during this time disrupts ontogenic trajectories. During the last decade, the use of prescription opioids during pregnancy has reached notably high rates (14- 22%) in the United States. While previous research has focused on the offspring for in utero effects of opioid use, the impact on the mother’s postpartum mental health has been largely overlooked. Notably, drug overdoses are one of the main preventable causes of pregnancy-related deaths, mainly occurring in this period. Here, we will assess the neurobehavioral changes caused by prescription opioid exposure during pregnancy and their postpartum impact on drug reward. The proposed work will focus on two key at-risk mechanisms during pregnancy: oxytocin and dopamine. Central oxytocin signaling by paraventricular hypothalamic neurons (PVNOXT) is halted during pregnancy and quickly re-initiated after parturition. Upon resumption of oxytocin release, ventral tegmental area (VTA)-projecting PVNOXT neurons promote attribution of incentive value to salient stimuli (e.g., pups). Therefore, VTA-projecting PVNOXT, which express µ-opioid receptors (µOR), represent a substrate for the pharmacological actions of prescription opioids (such as oxycodone) during pregnancy. We hypothesize that repeated activation of PVNOXT µOR leads to opioid tolerance and a long-term loss of inhibitory control over PVNOXT excitability, hence exacerbating VTA oxytocin release and altering dopamine function postpartum. We will use drug self-administration and neuroeconomic modeling to profile postpartum vulnerability to drug abuse in dams exposed to prescription opioids during pregnancy. Additionally, we will employ fiber photometry to examine in vivo changes in dopamine and oxytocin encoding of opioid rewards and electrophysiological tools to characterize PVNOXT synaptic alterations. Finally, optogenetic manipulations will address the sufficiency of the PVNOXT→VTA pathway to gate augmented postpartum reward-seeking behaviors in opioid-naïve mice. Together, these experiments will uncover novel behavioral and neural circuit aberrations resulting from prescription opioid exposure during pregnancy, focusing on the dam’s vulnerability to postpartum opioid abuse. Ultimately, this research proposal seeks to uncover a potential neurobiological mechanism linking the increased use of prescription opioids during pregnancy and the rise in postpartum overdose deaths.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY Injured corneal nerves can regenerate but in general, the resulting nerve repair is incomplete or may take years to recover their original density and patterning. While several growth factors can enhance the recovery of damaged corneal nerves and one of them has been clinically approved to treat corneal injuries (nerve growth factor), patients still complain about discomfort, dryness, and pain. These observations indicate that more complete anatomical and sensory regeneration of injured nerves may need to occur for patients to recover. Most likely the type/site/time of nerve injury affects the anatomical, molecular, and functional regeneration of corneal nerves. Therefore, the administration of clinically validated factors that enhance nerve regeneration, not only accelerates the rate of healing but also induces differential effects on functional nerve sensation. Since regeneration of corneal nerves requires multiple wound healing processes, the use of single agents may not be the best therapeutic approach, and combination of factors with similar or complementary roles may be necessary to accomplish repair at the morphological and functional levels. In this proposal, we hypothesize that secreted extracellular vesicles (including exosomes) derived from different sources differentially regulate the anatomical, molecular, and functional aspects of regenerating corneal nerves. To identify these changes, we proposed the following: Aim 1 will characterize the ability of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) to promote the anatomic and molecular regeneration of corneal nerves following mechanical and chemical injury. Aim 2 will evaluate the functional and behavior recovery of corneal nerves following administration of EVs. Aim 3 will elucidate the bioactive components of the extracellular vesicle’s cargo, which can lead to new therapeutic approaches for complete corneal nerve repair.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY The intestinal epithelium, constantly challenged by environmental toxins, chemicals, or pathogens, is continually being renewed and regenerated to maintain gut homeostasis through the proliferation and differentiation of intestinal stem cells (ISCs). When this regenerative process is impaired, particularly in response to injury, chronic inflammation and disease states such as inflammatory bowel disease may result. The matricellular protein CCN1 has emerged as an overarching regulator of multiple functions in intestinal repair and regeneration through its direct interactions with distinct integrin receptors in disparate cell types. Recently, we have shown that CCN1 coordinately regulates ISC proliferation and differentiation into distinct epithelial cell types through the regulation of Wnt and Notch signaling, in part by activating YAP, which contributes to epithelial regeneration in homeostasis. In our new supporting data, we observed that (1) Mice with Ccn1 deletion in Lgr5+ ISCs and knock-in mice expressing integrins αv-binding defective CCN1 suffer high mortality and impaired epithelial regeneration in dextran sulfate sodium (DSS)-induced injury. (2) Moreover, these knock-in mice fail to restore the ISC pool after diphtheria toxin receptor-mediated ablation of the Lgr5+ ISCs, indicating that CCN1 may be required for the reprogramming or dedifferentiation of epithelial cells into ISCs. (3) Although senescent cells are generally thought to be deleterious, mice treated with the senolytic drug ABT-263 to eliminate senescent cells sustain impaired epithelial restitution after DSS injury, and similar defects are observed in knock-in mice in which Ccn1 is unable to bind integrin α6β1 and are therefore unable to induce stromal fibroblast senescence. These findings suggest that senescent fibroblasts promote intestinal epithelial repair and CCN1 may be a key inducer of senescence. Based on these results, we will scrutinize the hypothesis that CCN1 is an overarching regulator of intestinal injury repair by controlling both the dedifferentiation of epithelial cells to restore the ISC pool and the induction of fibroblast senescence in the stroma through integrins αv and α6β1, respectively, with the following specific aims: (Aim 1) To analyze how CCN1 regulates cell dedifferentiation to restore the ISC pool upon injury and dissect the distinct functions of CCN1 and YAP in a regulatory loop to control this process. (Aim 2) To investigate the role of CCN1-induced stromal cell senescence in epithelial regeneration via the release of the senescence regenerative factors (SRFs). These studies will yield new insights into a powerful endogenous repair program that coordinately regulates complex cellular processes in various cell types for intestinal injury repair and pave the way for novel targeted therapeutics that promote intestinal repair and regeneration following injury.

NIH Research Projects · FY 2025 · 2024-03

Project Summary/Abstract Multimorbidity involving comorbid mental and medical chronic conditions such as depression and obesity is highly prevalent among middle-aged and older adults, disproportionately affecting racial and ethnic minorities. Depression and obesity contribute to greater cardiometabolic disease risk (e.g., diabetes), poorer treatment adherence, and worse quality of life than either condition alone. Both conditions are also risk factors for Alzheimer’s disease and related disorders. Behavioral interventions are traditionally designed to treat depression and obesity separately; however, few target both conditions. Moreover, scalability of traditional behavioral interventions is limited, and accessibility is generally poor, especially among racial and ethnic minorities. Our team previously demonstrated the efficacy of an integrated behavioral intervention for comorbid depression and obesity, I-CARE, which combined 2 proven treatments: an in-person problem-solving therapy (PST) for depression and a video-based behavioral weight loss intervention adapted from the Diabetes Prevention Program (DPP). Recently, we developed and pilot-tested Lumen, a first-of-its-kind, voice-based virtual coach for PST on Amazon’s Alexa platform. In a pilot randomized clinical trial of predominantly racial and ethnic minority participants, Lumen demonstrated high feasibility and usability and promising effects on depression and anxiety symptoms. The objective of the current project is to test the efficacy of a fully digital I- CARE intervention, combining the Lumen PST virtual coach for depression management with the DPP video- based program for weight loss. Patients (N=440) self-identified as a racial or ethnic minority with depression and obesity will be enrolled from a large minority-serving academic medical center in Chicago. In this fully remote clinical trial, participants will receive a tablet, a wireless weight scale, and a wearable activity tracker. Participants will be randomly assigned to the digital I-CARE intervention (with 6 months of active treatment and 6 months of maintenance) or waitlist control, and assessed at 6 and 12 months. Controls will receive active treatment in the digital I-CARE intervention after their assessment at 6 months (primary endpoint). Specific aims are to (1) determine the intervention effects on the primary depressive symptoms and weight loss outcomes, and on secondary outcomes (e.g., psychosocial and cognitive functioning); (2) identify predictors of treatment success, defined by clinically significant weight loss (5%) and depression response (50% symptom reduction) or remission (free of symptoms); and (3) characterize the experiences and perceptions of intervention participants to inform future development and translation. The proposed research is innovative, advancing minority aging research using digital health and focusing on integrated care to reduce depression, obesity, and related health risks specifically among racial and ethnic minority adults aged 50-74 years. This work aligns with NIA’s priorities to prevent multimorbidity and reduce health disparities through innovative interventions to maintain health, well-being, and function.

NIH Research Projects · FY 2026 · 2024-03

ABSTRACT The number of overdose deaths caused by stimulants like cocaine and methamphetamine has increased at an alarming rate over the last decade. Yet, unlike other addictive substances, such as alcohol, nicotine, and opioids, there are currently no FDA-approved medications for stimulant use disorders, leaving millions of Americans without an effective therapeutic treatment. Growing evidence indicates that the α3β4 subtype of the nicotinic acetylcholine receptors (nAChRs) play an integral role in drug addiction and that selective inhibition of these receptors reduces the addictive properties of cocaine, methamphetamine, and other drugs of abuse. However, existing classes of α3β4 nAChR antagonists suffer from poor selectivity, are not brain-penetrant, or induce partial activation of the receptor, which hinder their clinical development. The objective of this proposal is to develop a novel class of α3β4-selective nAChR negative allosteric modulators (NAMs) based on the alkaloid aristoquinoline and demonstrate their effects in animal models of cocaine use disorder. Preliminary data generated in our lab indicate that aristoquinoline and its derivatives potently and selectively inhibit α3β4 nAChR activation and significantly reduce drug-seeking behavior in an animal model of cocaine relapse. The proposed studies will build upon these results by testing the central hypothesis that α3β4 nAChRs NAMs based on the aristoquinoline scaffold can safely and effectively reduce the addictive properties of cocaine. Aim 1 will optimize the α3β4 potency and selectivity of aristoquinoline by generating a collection of rationally designed derivatives and evaluating their affinity and functional activity. Aim 2 will locate the aristoquinoline allosteric binding site, define the mechanism of action, and identify off-target liabilities. Aim 3 will translate these results in vivo by prioritizing lead compounds with optimized drug-like properties and advancing them into preclinical safety studies and efficacy models of cocaine self-administration and relapse. This research is innovative, as it seeks to address and overcome the limitations of existing α3β4 antagonists by investigating an understudied class of nAChR ligands with a unique mechanism of action. The results from these studies will be significant because they will produce the ideal pharmacological probe for investigating the function α3β4 nAChRs in vivo and deliver promising drug leads for the treatment of cocaine use disorder.