Oregon Health & Science University

NIH Research Projects · FY 2026 · 2025-05

Project Summary / Abstract The Medicines for Malaria Venture (MMV) recently published a “roadmap” for the types of medicines that are needed to support the long-term goal of malaria elimination and eradication. The roadmap consists of a wish list of target candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the anti-malarial target candidates and product profiles the MMV highlighted the need for identifying new rapid acting medicines for active case management while other drugs are needed for chemo-protection and chemo- prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver- stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex ELQ-300 selectively targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. Unlike atovaquone, ELQ-300 is a selective inhibitor of the Qi site of the targeted enzyme complex. With support from the NIH and US DOD we created a prodrug, ELQ-331, that is more effective in vivo due to improved oral bioavailability. This drug has been accepted by the MMV as a Preclinical Candidate for once-weekly dosing for disease prevention. We have now identified ELQ-596 with significantly improved intrinsic anti-plasmodial activity in vitro, enhanced efficacy in vivo in a mouse model of the disease and a more extended bloodstream half-life relative to its progenitor. This application seeks support for optimizing the structural features of ELQ-596 to provide a Next Generation of ELQs for once-monthly oral prophylaxis in humans. This would simplify the dosing regimen, improve compliance, decrease the dose and associated costs, and improve outcomes. Superior molecules will advance through a down-selection test cascade for assessment of selective potency and lack of mammalian cytotoxicity, metabolic stability, solubility in simulated intestinal fluids, resistance propensity and mode of action as well as efficacy against blood and liver stage malaria in mice. Prodrugs of superior molecules will be explored to assess for enhanced oral bioavailability and antimalarial performance over parent molecules. Scientists with expertise in the following areas make up the collaborative investigational team: medicinal chemistry, malaria, molecular parasitology, biochemistry, structural biology, and pharmacology.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common condition characterized by persistent sinonasal mucosal inflammation resulting in visible polyps, cardinal symptoms such as nasal congestion and loss of smell, and a significant reduction in quality of life. The development of biologic medications over the last 5 years has revolutionized the treatment of CRSwNP. However, data from industry clinical trials does not show universal improvement and ideal control of disease across all patients with CRSwNP. This should not be surprising in light of our recent data showing up to 40% of patients with CRSwNP do not have a classic Type 2 endotype. As expected, phase III clinical trials were designed primarily to achieve regulatory approval and broad indications. The result is that we have no way of knowing which specific biologic would be the best option for any given patient, nor do we know whether biomarkers can be used to predict response to biologics. These persistent gaps in understanding have resulted in an unfortunate treatment paradigm where clinicians empirically choose a biologic and wait to see if the patient benefits. Considering the extreme cost of biologic medications and need for long-term treatment, this non-selective utilization of a selective medication represents a current clinical problem and unmet scientific need. Therefore, the primary objective of the proposed study is to compare clinical outcomes across specific biologics. Furthermore, we hypothesize that biomarkers can be used to identify patients most likely to improve on biologic therapy. These hypotheses will be tested via a pragmatic, multi-arm, randomized clinical trial. Patients with CRSwNP who have elected to pursue biologic therapy will be enrolled and rigorous baseline data obtained including sinonasal mucus for biomarker assessment. Patients will be randomized 1:1:1 to one of three treatment arms (dupilumab, omalizumab, or mepolizumab). The primary outcome is change in sinonasal quality of life (SNOT-22) after 24 weeks of treatment. Key secondary outcomes include change in nasal congestion score, polyp grade, and olfaction after 24-weeks of treatment. An additional analysis will determine whether changed in the primary outcome at 24- weeks can be predicted using mucus biomarkers collected at baseline in the clinic setting. Successful completion of this trial will help answer some of the most pressing clinical questions related to biologics and CRSwNP. Specifically, findings will inform whether any one biologic has superior outcomes to another, whether clinicians can identify patients at baseline who are most likely to improve on biologic therapy, and finally whether mucus biomarkers can predict a patient’s response to biologic therapy.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Cues associated with drugs of abuse are powerful triggers of craving and relapse, and increased reactivity to such cues is a core feature of substance use disorder. To understand mechanisms that support cue-induced cocaine craving, we use the incubation of craving model, in which rats exhibit progressive intensification (incubation) of cue-induced craving during the first weeks of withdrawal from cocaine self-administration (SA); craving then remains elevated for months, modeling persistence of vulnerability in recovering cocaine users. We have shown that, after ~1 month of withdrawal, incubation depends on persistent strengthening of AMPAR synaptic transmission in nucleus accumbens core (NAcc) which in turn depends on tonic dysregulation of protein translation during withdrawal. On top of withdrawal-dependent changes, we found that additional rapid translation is evoked when `incubated' rats are re-exposed to cocaine cues, and that this additional translation is required for these cues to elicit expression of incubated craving. Nothing is known about mRNAs differentially translated during cue re-exposure, a significant gap since translation is required for the incubated craving response. Aim 1 will fill this gap by using translating ribosome affinity purification to isolate actively translating mRNAs, which will then be analyzed by RNA-seq (TRAP-seq). The two main subtypes of NAcc medium spiny neurons (MSN), expressing D1 or D2 DA receptors, will be studied using a Cre-dependent TRAP virus and D1-Cre or adenosine 2a (A2a)-Cre rats (the A2a receptor is a marker for D2 DA receptor-expressing MSN). MSN subtypes must be distinguished because they regulate behavior via complex and sometimes oppositional interactions, and because they exhibit distinct synaptic plasticity after incubation of cocaine craving. Male and female D1- or A2a- Cre rats will self-administer saline or cocaine (6 h/d x 10 d; each infusion paired with a light cue). They will then undergo a 15-min cue-induced seeking test on withdrawal day (WD) 1 (baseline craving) or WD40 (after incubation). NAcc will be collected immediately and processed for TRAP-seq to identify mRNAs that are actively translating during the period of cue exposure. Translating mRNAs specific to the cocaine WD40 group are strong candidates for mediating the incubated response to cocaine cues, particularly since we can compare to existing data on translating mRNAs from rats that did not receive a seeking test in order to distinguish seeking test- induced from withdrawal-induced changes in translation. In Aim 2, we will select ~10 such translating mRNAs for validation at the mRNA and protein levels using qPCR and Western blotting, respectively. This proposal fits the R21 mechanism, as it breaks new ground methodologically (first to combine TRAP-seq, transgenic rats, and a translationally relevant cocaine SA model) and conceptually (first exploration of rapid protein translation elicited by a drug-associated cue in any cell type).

NIH Research Projects · FY 2026 · 2025-04

Project Summary Highly active antiretroviral therapy (ART) has dramatically improved survival and reduced progression to AIDS for people-living-with-HIV (PWH). However, PWH remain at significantly increased risk for diseases associated with chronic systemic inflammation, such as coronary artery disease, stroke, cognitive disorders, and some malignancies. Substance-use-disorders (SUD) are associated with HIV-disease progression, regardless of ART use. Understanding if and how opioids impact immunity among PWH is important due to the increased risk of opioid-use-disorder (OUD) among PWH, and the vulnerability of PWH to co-morbidities driven by immune dysregulation. This proposal aims to determine if chronic opioid exposure (COE) among PWH who are experiencing OUD is a driver of dysregulated innate immunity. Our published work and preliminary data demonstrate that monocytes are vulnerable to opioid-associated disruption of both pro- and anti-inflammatory functions among PWH, regardless of HIV viral load. In this dissertation proposal, I will address my hypothesis that COE among PWH results in increased reliance on glycolysis during a resting state, disruption of mTORC1 signaling, and impaired metabolic plasticity in response to stimulation that compromises both pro- and anti- inflammatory monocyte functions. Findings from this proposal will open the door for therapeutics that ameliorate opioid-induced monocyte dysregulation and advance our understanding of the off-target effects of long term opioid-exposure.

NIH Research Projects · FY 2026 · 2025-04

Abstract Circadian disruptions like shift work are associated with reproductive health difficulties including infertility. When estrogen is high, the circadian system triggers the pre-ovulatory luteinizing hormone (LH) surge at lights-off in humans and rodents. These rhythms are perturbed, however, when food is eaten during the rest phase, as is common in shift work. In rodents, mistimed food reduces fertility by 30% and disrupts the normal timing of mating behavior and ovulation, but the mechanisms are not known. We will test the hypothesis that misalignment of light and food cues compromise the function of kisspeptin neurons of the anteroventral periventricular nucleus (AVPVKISS) and prevent the normal timing of the LH surge. First, in Aim 1, we will map AVPVKISS monosynaptic projections for the first time with a paired adeno associated virus and G-deleted rabies virus in Kiss1Cre mice. We have confirmed that AVPVKISS afferent neurons are located in areas that include the suprachiasmatic nucleus (site of the central circadian clock) and the arcuate nucleus (key area in feeding regulation). By mapping this circuit, it will give us insight into regions important for the induction of the LH surge and will provide our lab and the field with new mechanistic targets. In Aim 2, we will investigate whether food-sensitive arcuate AgRP and POMC neurons link mistimed food to the desynchronized LH surges. These cell groups are complementary orexigenic and anorexigenic neurons that project to the AVPV, and the AgRP cells have previously been shown to encode food timing. We will test the effect of silencing these neurons specifically during conditions of food restriction with the prediction that this will relieve the pressure of mis-timed food and rescue the normal synchronized LH surge time. Together, these experiments will establish candidate inputs to the regulation of ovulation and establish the role for food sensitive neurons in transducing food intake rhythms to rhythmic physiology and behavior. This research project provides an opportunity for learning the theory and techniques of modern systems neuroscience through the lens of reproductive neuroendocrinology. The proposed experiments will provide fundamental training in neural reproductive research and enable the study of circadian control of other neuroendocrine signaling systems in the future. Further career development training will include writing and reviewing manuscripts, didactic coursework, pedagogy and mentoring training, and opportunities to present the results and network at OHSU symposia and at national meetings. The training will take place in the Neuroscience Graduate Program's collaborative and supportive environment within the Vollum Institute at OHSU.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Approximately 38 million Americans have a hearing impairment. While hearing devices such as hearing aids (HAs) and cochlear implants (CIs) are successful in improving speech recognition for many hearing- impaired individuals, there is still significant variability in benefit, and speech recognition in noise remains a problem. One factor that may limit benefit, especially binaural benefit, is abnormal binaural integration of both spectral and temporal information. A prerequisite for binaural integration is binaural fusion — the fusion of stimuli from the two ears into a single auditory object. Unlike normal-hearing (NH) listeners, we have shown that many HA and CI users experience abnormally “broad” binaural fusion in the spectral domain, such that pitches that differ greatly in frequency between the two ears are still heard as a single percept. Individuals with broad fusion also experience abnormal binaural spectral integration - averaging and thus distortion of spectral information across the ears when disparate sounds are fused. Broad fusion has been shown to be associated with binaural interference — poorer speech recognition with two ears compared to one. Most importantly, we demonstrated recently that broad fusion is associated with greater difficulty with understanding speech in challenging multi-talker listening situations, such as noisy restaurants. Difficulties with speech understanding in noise is a major complaint of both HA and CI users. These results demonstrate the high clinical significance of abnormal binaural fusion for the difficulties that listeners with hearing loss and hearing devices experience with speech perception in background noise. However, some gaps remain in our understanding of binaural fusion, especially in individuals with hearing loss. Do HA and CI users also differ from NH listeners in binaural fusion in the temporal domain, and if so, how does this affect speech recognition? Another major gap is in how to treat abnormal binaural fusion. There is unexplored potential for top-down and multi-sensory cues to be used as supplementary cues to help reduce abnormally broad binaural fusion. Thus, the goal of this proposal is to address these gaps in our understanding of: 1) how listeners with hearing loss differ from NH listeners in binaural fusion of temporal and spectro-temporal information (Aim 1), and 2) whether top-down and vibrotactile cues can sharpen binaural fusion, with potential application for rehabilitation (Aim 2). The findings will provide broader insights into the neural mechanisms underlying binaural fusion, and establish a framework for future treatments to sharpen binaural fusion to maximize binaural benefits and improve speech perception in noise.

NIH Research Projects · FY 2026 · 2025-04

Project Summary: Up to 4000 collegiate athletes annually sustain a concussion in the United States. Sleep-wake disturbance (SWD) is one of the most common complaints following a concussion. Athletes who report post-concussive SWD also report worse somatic and cognitive impairment and a longer recovery time. Unfortunately, the current therapies aimed at improving sleep in patients with concussions are limited by poor compliance and low efficacy. Our long-term goal is to target post-concussive SWD as an independent, modifiable risk factor for poor outcomes in collegiate athletes and other at-risk populations. In this study, we aim to answer two fundamental questions. First, among student-athletes, who is at risk for developing post-concussive SWD? Second, what are the biological mechanisms linking post-concussive SWD and poor outcomes? Answering those questions will advance our field by 1) allowing early identification of at-risk subjects and 2) establishing therapeutic targets for the thousands of patients who, despite their best attempts, still struggle with poor sleep following a concussion. This proposal focuses on the glymphatic pathway as a potential biological link between post-concussive SWD and poor outcomes. The glymphatic pathway is a network of perivascular spaces that supports the clearance of cerebral interstitial molecules and wastes during sleep. In animal models, concussion and sleep restriction impair glymphatic function, worsening neurological function. However, the combined effects of concussion and post-concussive SWD on glymphatic function in humans remain unknown. We hypothesize that concussion and post-concussive SWD have a multiplicative impact on glymphatic function impairment (i.e., a 'double hit' mechanism). We use magnetic resonance imaging (MRI) to measure human perivascular spaces. The number and volume of these structures (i.e., their burden) have been proposed as a surrogate marker of glymphatic function. In addition, we recently developed other MRI modalities to assess different facets of glymphatic function. To test our hypotheses, we will track sleep in a cohort of collegiate athletes during the sports season using actigraphy and a contactless bed mat sensor. We will also obtain a polysomnogram and an MRI fourteen days post-injury in those with a concussion and controls with musculoskeletal injuries. We will use advanced neuroimaging techniques to measure various aspects of glymphatic function, including perivascular space burden, contrast clearance, water diffusion, and slow vasomotor oscillations. We propose the following aims: in collegiate athletes, 1) define the pre-morbid risk factors for developing post-concussive SWD; 2) establish the combined effects of concussion and post- concussive SWD on perivascular space burden; 3) determine the association between post-concussive SWD and non-invasive, clinically available neuroimaging markers of glymphatic dysfunction. Results from this study may help identify at-risk subjects and provide the rationale for targeting glymphatic function (pharmacologically or via other interventions) to prevent post-concussive morbidity in athletes and other populations.

NIH Research Projects · FY 2026 · 2025-04

Three out of ten women in the US are obese prior to becoming pregnant. Obese pregnant women face increased risk of obesity and metabolic disease in their newborns, thus initiating a vicious trajectory of obesity and its health-related consequences in subsequent generations, a phenomenon called developmental programming. Epidemiological studies show a strong link between maternal obesity and the offspring's increased risk of metabolic and cardiovascular diseases; however, efforts to prevent such programming have been confounded by an incomplete understanding of the underlying mechanisms. We have previously developed and reported a mouse model of maternal high-fat diet (HFD)-induced adiposity that recapitulates cardio-metabolic abnormalities seen in human offspring of obese mothers. We found that metabolic dysregulations including obesity, glucose intolerance, and asthma, progress in the adult offspring of mothers fed a HFD—all despite the offspring eating a regular diet only and having similar food intake and activity levels as the offspring of regular diet-fed mothers. Our new data from this mouse model suggest that in comparison with regular diet-fed dams, pregnant HFD-fed dams present increased inflammation that also includes excessive production of interferon-gamma (IFN-), a pro-inflammatory regulator of macrophages. Furthermore, our metabolomics analysis showed significant metabolic perturbations in bone marrow cells isolated from newly weaned offspring of HFD-fed mothers, similar to those previously reported in aging. Those changes included activation of glycolysis and oxidative phosphorylation and decreased amino acid levels. Furthermore, in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, we found increased expression of COX2 on myeloid cells, and identified a unique B-cell population expressing CD19 and CD11b, that was significantly more abundant than in offspring of a regular diet-fed mothers. Thus, our data indicate that immunometabolic and immune perturbations precede the progression of adult metabolic diseases in the offspring of obese mothers. The finding that inflammation potentially mediates the pathological consequences of maternal obesity in offspring raises the hope of exploiting existing anti-inflammatory drugs to treat individuals with maternal obesity-associated metabolic disorders. Underscoring this potential, administration of low-dose aspirin in pregnant women has been shown to lower the risk of preeclampsia, an inflammatory condition. The overall hypothesis of this study is that increased inflammation in HFD-fed mothers causes early-life immunometabolic reprogramming in offspring, thereby leading to metabolic diseases in later life. Two specific aims are proposed. In Aim 1, we will conduct a pre-clinical trial of using low-dose aspirin in regular and HFD-fed pregnant female mice with the scope of reducing the later life risk of obesity and metabolic diseases in their offspring. In Aim 2, we will determine whether the metabolic dysregulations in bone marrow cells in 3-week-old offspring of obese mothers cause chronic inflammation and metabolic disease in adulthood.

NIH Research Projects · FY 2025 · 2025-03

This is a supplement application for Biomarker, Imaging and Quality of Life Studies Funding Program (BIQSFP) funding for the following SWOG Cancer Research Network studies: S1608, S1803, S1806 (NEW), S1827, S2114, S2212, and S2312. Additionally, this request contains the progress reports for the following additional studies: S1418, S1602, S1826, and CTIU 23-18.

NIH Research Projects · FY 2026 · 2025-02

Summary Glaucoma, a major blinding optic neuropathy, is a progressive, debilitating disease with visual field loss. The primary risk factor for the disease, as well as the one and only treatable parameter to delay bilateral blindness and slow the disease is to reduce the elevated intraocular pressure (IOP). The IOP is controlled and adjusted by the resistance to aqueous humor outflow. This resistance resides within the deepest portion of the trabecular meshwork (TM), called juxtacanalicular (JCT) region, and in the greater basement membrane of the inner wall cells of Schlemm's canal endothelium (SCE). IOP changes are sensed by JCT cells as mechanical stretching, and they react by modifying the outflow resistance to restore the IOP to normal. This is the IOP homeostatic response. However, this IOP homeostatic response is lost in glaucomatous eyes. In glaucoma there is also significant TM cell loss. We developed a model for human anterior segment TM cell loss, and in this model, IOP homeostasis is compromised. Transplanting TM cells, differentiated induced pluripotent stem cells, or human mesenchymal stem cells in this ex vivo model restores IOP homeostatic regulation. TM cells become senescent with increased passage in culture or with exposure to H2O2. Aged glaucomatous TM cells exhibit much higher levels of senescence than normal aged TM cells in tissue. Presumably, these senescent cells are occupying space in the TM but are not facilitating the IOP homeostatic response or may even be diminishing it. Transplantation of stem cells into the TM where many senescent cells are present may diminish how many stem cells can attach and integrate to restore IOP homeostatic function. Senotherapeutics are recently developed drugs which act upon the senescent cells. Senolytic pharmaceuticals can selectively clear senescent cells removing them from occupying tissue space or can reverse some of the negative changes that are characteristic of senescent cells. Senoreverters can reverse the properties of senescent cells and restore some or complete function. This might include restoration of lost IOP homeostatic capability. Herein, we propose to use senolytics and separately senoreverters to restore TM cell IOP homeostatic function to glaucomatous tissue with or without the assistance of stem cell transplantation. This has the potential to lead to new innovative therapies to restore glaucomatous IOP homeostatic capability.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY (Abstract) The integrity of the tympanic membrane (TM, eardrum) is essential for sound transduction and hearing. TM also serves as a protective barrier between the external auditory canal and the middle ear against invading pathogens. TM perforation, damage-induced otitis media, and conductive hearing loss are common clinical problems affecting millions of people worldwide. Macrophages, the first line of innate immune defense, are distributed in all organs and tissues of the body, including the eardrum. They are essential in tissue development, homeostasis, inflammation, and repair. However, the specific role of macrophages in TM biology under steady- state and injured conditions has been largely overlooked and remains poorly studied. When studying macrophages in the inner ear, we captured the large population of tissue-resident macrophages (TRMs) embedded in the TM. The TRMs in the neonatal stage largely colonized `nascent' blood vessels and `underdeveloped' peripheral nerve bundles. Their population dropped, and morphology notably changed from neonate to young adult. Postnatal development of the TRMs intriguingly paralleled vascular maturation and neuronal development. When the TM is acutely perforated in adults, monocyte-derived macrophages rapidly congregate in the wound area and angiogenesis is initiated. Our pilot data also reveal the TM is remarkably rich in TRPV1+ sensory nerve fibers. Our bulk RNA seq data shows high upregulation of Tac1 (Tachykinin Precursor 1, encoding for tachykinin neuropeptides such as substance P and neurokinin A) in the perforated TM at an early stage of injury. Neuropeptides are primarily secreted by neurons following injury. These initial findings raise fundamental questions: What is the origin of the neonatal TRMs? Are they critical for the postnatal development of the TM and required for vascular and neuronal maturation? What molecular signal elicits monocyte recruitment and angiogenesis? Does TM injury activate TRPV1+ neurons to release Tac1-encoded neuropeptides, stimulating wound healing by promoting macrophage recruitment and angiogenesis? To address these questions, we will use a comprehensive set of cutting-edge research methodologies, including genetic fate mapping, chimeric bone marrow transplantation, high-resolution OCT, and genetic mutation, to thoroughly investigate the embryonic source of TRMs, their core function in postnatal TM development, and the molecular signaling involved in adult TM wound healing. Characterization of the origin, diversity, and postnatal dynamics of macrophages in the TM will reveal the previously unknown complexity of macrophage biology. In particular, it will reveal how the innate immune system in the TM is constructed, how it is maintained, and how it functions. Identification of the molecular signaling in TM wound healing in this project will also spur the development of new therapeutics to facilitate the repair of damaged TM.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT There is a significant unmet need to train both basic and clinical researchers in the skills needed to pioneer novel translational research and develop the next generation of innovative cancer therapeutics. The proposed Experimental Therapeutics in Cancer (ETC) training program will leverage the research and training strengths of the Knight Cancer Institute (KCI), an NCI-designated Comprehensive Cancer Center at Oregon Health & Science University (OHSU), to provide an immersive 2-year postdoctoral training program in oncological drug development. OHSU was recently ranked among the top young universities in life sciences research in the world in the Nature Index and, notably, OHSU and the Knight Cancer Institute are home to the Center for Experimental Therapeutics (CET) that serves as a central hub for discovering and developing new cancer treatments to improve patient outcomes. The ETC training program brings together resources and a multidisciplinary group of preclinical and clinical mentors and trainees to accelerate the translation of scientific discoveries into effective therapies. A key strength of the training program will be fostering collaboration and communication between the basic and clinical science spheres. The program offers interprofessional training for PhD and MD postdoctoral fellows with required co-mentorship by both basic and clinical faculty. We propose to train a total of 9 individual PhD and MD scientists in this two-year program to position them for successful careers in translational oncology. ETC trainees will participate in preclinical research projects focused on designing novel molecules, validating therapeutic targets, performing lead optimization, developing biomarkers, and/or studying agents in preclinical models. In addition to course work, including Drug Discovery and Development and Responsible Conduct of Research, PhD and MD trainees will participate in clinical rotations and learn early phase trial design and related regulatory requirements. The program emphasizes professional skills development, including oral and written communication and grant preparation. Trainees will have a supported opportunity to develop mentorship skills through mentoring a summer intern from one of the pathway programs at OHSU/KCI designed to increase the participation of students from backgrounds underrepresented in biomedical research. The 37 training faculty in the program have broad experience in oncology research, therapeutic development, and translational medicine. ETC training faculty have outstanding track records in mentorship and research, with an average of >$1,000,000/year in research funding. The ETC program is designed to train the next generation of translational investigators in oncology with the necessary skills to translate preclinical research into novel therapeutics to reduce the burden of cancer.

NIH Research Projects · FY 2025 · 2025-01

Project Summary The overarching objective of this R25 program is to develop the curricular materials for teaching essential data science skills to early career scientists interested in microbiome research to enable them to access and use data available in the Common Fund Data Ecosystem (CFDE). Although there is an enormous potential for the large datasets available through the CDFE to advance biomedical research, our broad needs assessment has identified that a wide range of researchers lack fundamental skills necessary to use these types of data. Gaps we have identified include identifying the appropriate data sets to answer hypotheses, managing, wrangling, and harmonizing data in preparation for analysis, in addition to performing the analyses. We propose to close this gap and accomplish our objects by: 1) Performing a needs assessment of potential Common Fund Data users, targeting early career clinically oriented faculty developing research related to the human microbiome. 2) Developing curricular materials for knowledge and skills in data science using three datasets developed by NIH Common Fund projects related to the human microbiome, microbial products, and clinical associations. 3) Delivering a two-week in-person short course on data science to a diverse set of early career learners to educate and provide skills necessary for accessing data in the Common Fund Data Ecosystem and incorporating these data sources into research. And 4) Providing extended support beyond the short-course through informatics mentorship to support common fund data use in participant’s area of research. The program will be led by experts in Biomedical Informatics Education and Microbiome Bioinformatics and be supported by several faculty with expertise and extensive educational experience in data science, clinical informatics, artificial intelligence and machine learning, data visualization, and data management. The short course will focus on applications of CFDE to address research questions related to the human microbiome in human health and disease, with a specific focus on diabetes. We anticipate the impact of this program to be substantial in enabling researchers to improve their use of existing CFDE projects into their own research more rapidly and accurately. We will disseminate this work broadly through online resources so that others may train their own teams.

NSF Awards · FY 2025 · 2025-01

This project builds and tests new technology to help people with severe speech and motor impairments better control computers and use them to communicate. Such impairments make it very hard to use voice, touch, keyboard, and other common ways of interacting with computers. One alternative that can help is "single-switch" interaction, where systems allow people to use the muscle control they do have to simulate clicking a single button. For instance, Stephen Hawking famously composed lectures and interview responses with his computer by twitching his cheek; other interfaces use blinking, or puffing air into a special sensor. However, these single-switch interaction methods, and the interfaces built based on them, are much slower and more error-prone than voice, touch, or keyboard interfaces. In this project, the research team collaborates with people with severe disabilities to develop technology to make it faster, easier, and more accurate for this set of people to communicate and use computers. The key general idea is to use additional information about a person's context such as where they are looking, what they have done recently, and other clues to their intentions to help computers guess, and suggest, complicated communication goals based on simple single-switch interactions. To meet these goals, this project leverages machine learning and a novel user interface to synthesize four currently under-utilized information sources. First, users are likely to be looking at a target when they select it; unlike methods that use eye gaze as a pointer, such passive information requires no conscious eye effort from the user and may provide information even when a user's gaze is not precise enough for selection by itself. Second, modern large language models can often anticipate what a user is interested in writing and can likely learn to leverage contextual clues (e.g., who the user is writing to or topics suggested by a communication partner) with only a small number of training examples. Third, patterns of behavior across users and time can offer clues; for example, similar users may provide information about a new user, or a user might exhibit different behaviors at different times of the day. Fourth, sequences of noisy input actions can jointly inform a desired user action such as writing a word. The project combines these four sources of information with a user's single-switch input to improve speed and accuracy of text entry and computer interaction tasks. This project's innovations are designed and tested with users with disabilities in an extensive, multi-pronged set of participatory design activities and experiments. Participatory design with this set of users is particularly challenging due to their communication speed. This project therefore investigates a novel combination of participatory design methods in which stakeholders provide feedback via an asynchronous messaging platform, in co-design interviews, and via surveys designed to be easily completed with single-switch interaction techniques. 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 · 2025-01

Project Summary One in three Medicaid enrollees has a diagnosed mental health condition, yet this population faces substantial mental health service gaps. Low Medicaid reimbursement is thought to be one key factor limiting the available mental health specialists willing to accept Medicaid enrollees, contributing to these access gaps. However, there have been strikingly few investigations on how payment amounts affect provider participation and enrollee utilization and outcomes in Medicaid. Studies drawn mostly from primary care have yielded mixed results, and it is unclear that findings in the primary care literature extend to mental health care, which faces unique systemic and workforce constraints. Without rigorous study, policies using reimbursement to address Medicaid mental health workforce shortages may fail to achieve their intended effects. Against these knowledge gaps, we propose a 5-year mixed-methods research agenda that uses national Medicaid claims data coupled with in-depth qualitative interviews to leverage a real-world natural experiment: beginning in 2022, multiple state Medicaid programs have implemented reimbursement increases for mental health services in an effort to expand the mental health workforce and improve access to care. This explanatory sequential mixed methods proposal thus focuses on key questions critical to policymakers: 1) to what extent do mental health reimbursement rate increases change provider behavior and patient health, and 2) under what conditions do they work well? In Aims 1 and 2, we use 2016-2025 national Transformed Medicaid Statistical Information System (T-MSIS) Analytic Files (TAF), which provides comprehensive enrollee-level claims data related to service utilization and prescription use. We use an event study difference-in-differences framework to assess changes in outcomes for Medicaid enrollees exposed to reimbursement increases across dimensions of magnitude (how large are rate increases?) and scope (to what services do rate increases apply?). Aim 3 provides added explanatory depth on the policy heterogeneity of reimbursement rate increases, through key informant interviews with state Medicaid administrators and mental health providers. We will select up to 8 states where reimbursement increases are associated with improvements in Medicaid provider participation (positive deviance states), and 8 states where they are not (negative deviance states). A number of innovations, including assessment of policy heterogeneity across states, consideration of market factors and claims-based measures of administrative burdens that influence provider decisions, and inclusion of both psychiatrists and psychiatric mental health nurse practitioners, provide a comprehensive and robust assessment of mental health rate increases, a key priority for state Medicaid programs and policymakers. In collaboration with an advisory committee of Medicaid and mental health policy stakeholders, results will provide actionable, impactful evidence to guide timely policies within a constrained mental health delivery system. 1

NIH Research Projects · FY 2026 · 2024-12

Project Summary Early life sleep is fundamental to the development of affiliative behavior, defined as any behavioral display that promotes positive social engagement. Autism spectrum disorder (ASD) is characterized by persistent changes in social behavior, sensory sensitivity, and sleep disruption. Additionally, excitatory, and inhibitory neuronal activity (E/I balance) is altered in ASD. Increased expression of parvalbumin-positive inhibitory interneurons and the appearance of extracellular structures, perineuronal nets (PNNs) surrounding these cells mark the functional maturation of the sensory cortex. The highly social prairie vole is an excellent model with which to study the relationship between early-life sleep and the development of neural circuitry underlying the display of affiliative behavior. Unlike mice and rats, prairie voles demonstrate species-typical familiarity preference demonstrated by side-by-side huddling in a novel environment. Our lab has shown early-life sleep disruption (ELSD) in prairie voles impairs species-typical affiliative behavior (huddling) and increases PV interneurons (PVIs) in the somatosensory cortex of adults. However, we do not know how ELSD impacts the early display of affiliative behavior nor how PV interneurons may mediate this early behavioral development. Our understanding of social behavior has been largely limited to manual scoring using a fixed set of identifiers. Use of novel computational tools for the objective discovery of affiliative behavior will allow for a more comprehensive understanding of subtle cues in this complex behavior during development. Thus, I propose to investigate the development of affiliative behavior between same-sex siblings (Aim 1) and PVIs (Aim 2) of male and female prairie voles across adolescence (P28-42) following ELSD (P14-21) or the Control condition. Characterizing the trajectory of both brain and behavior is expected to provide key insights into the functional role of early-life sleep in social development. The central hypothesis of this work is that, early-life sleep disruption alters the maturation of PV interneurons and results in reduced affiliative behavior between siblings during development. To understand the mechanisms underlying the timing of PV expression and affiliative behavior, we will randomize animals to standard housing versus an enriched environment (Aim 3) to probe potential rescue of brain and behavioral changes induced by ELSD. Identifying the molecular trajectories by which ELSD changes typical affiliative behavior and how enrichment modifies these social impairments may enable a better understanding of mechanisms underlying successful therapies for children with ASD.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The human brain has undergone many specializations (e.g., increased synapse density) resulting in unmatched cognitive complexity, as well as increased vulnerability to neurodevelopmental disorders, such as autism. Differences in gene expression are responsible for most human-specific brain specializations, and comparative (epi)genomics strategies are remarkably powerful in identifying the mechanisms underlying these differences. Spatial genome conformation, particularly organization of topologically associated domains (TADs), is a very promising candidate mechanism for driving human-specific gene expression patterns in the brain but remains understudied in this context. In our preliminary comparative investigation, we found that human-specific TAD organization in lymphoblastoid cells are associated with neurodevelopmental genes, and are recurrently disrupted in patients with developmental delay. However, genome conformation differs drastically across tissues, thus accurate identification of human-specific TAD organization and understanding its contributions to neuronal development and pathology can only be achieved by investigating genome conformation in brain cells. To this end, here we will analyze well-validated cortical neuroprogenitor cells (NPCs) and glutamatergic neurons in human and other primates to identify human-specific TAD boundaries, predict their functionality through in silico mutagenesis, and validate their contribution human neurodevelopmental specialization and disease by using targeted genome editing. In Aim 1, we will obtain Hi- C data from cortical NPCs and mature neurons derived from induced pluripotent stem cells (iPSC) of human, chimpanzee, orangutan, and rhesus macaque using well-validated differentiation protocols. Human-specific TAD boundaries identified in these cells will also be compared against primary NPC and neuron data to validate findings in-vivo. We will complement our findings with epigenetic and transcriptomics data from the same cells and species, to identify differential gene expression and genomic and epigenetic signatures associated with human-specific TAD organization. In Aim 2, we will use novel computation tools to predict effects of disrupting each human-specific boundary and prioritize 15 candidates whose disruption is most likely to cause neuropathogenicity. We will use CRISPR-Cas9 to delete these candidates in human iPSC-derived NPCs and neurons. The molecular consequences of each deletion on chromatin interactions/structure and gene expression will be assessed, along with electrophysiology (for neurons) or proliferation assays (for NPCs) to study the physiological consequences. We will then select a subset of 5 most effective candidates and knock them into chimpanzee iPSC, followed by differentiation to NPC and neurons. “Humanized” chimpanzee cells will be characterized at the molecular and physiological level like the human knockout lines, to further shed light on the function of human-specific TAD boundaries to human neurodevelopment. Overall, this study will provide new insights into mechanisms underlying human-specific brain development and disease.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The overarching goal of this proposal is to expand fundamental knowledge of bone repair mechanisms and improve regenerative strategies for craniofacial bone repair by investigating microenvironmental factors influencing osteogenic differentiation and bone regeneration. This work will employ a variety of biomimetic hydrogels, designed to recapitulate the extracellular matrix during distinct stages of bone formation: (1) soft collagen represents the initial matrix where undifferentiated stem cells reside, (2) high-density collagen reflects mesenchymal condensation, (3) partially mineralized high-density collagen simulates onset of calcification, and (4) a fully mineralized state indicative of mineralized woven bone. My preliminary data shows an early onset of osteogenic differentiation in human mesenchymal stem/stromal cell (hMSC) cultured on biomineralized hydrogels. However, the mechanisms to explain this accelerated regenerative response has not been thoroughly investigated. I hypothesize that increased in matrix density and mineralization will enhance osteogenic differentiation and bone regeneration. This hypothesis will be tested via Aim 1 by looking at adhesion-driven mechanotransductive mechanisms in vitro and Aim 2 by evaluating the in vivo bone healing response. Specific Aim 1 will examine the effect of the hydrogel model on osteogenic differentiation, focusing on the molecular clutch of mechanotransduction – a process where mechanical stimuli from the microenvironment is translated into biochemical activity, prompting cellular responses. This aim will evaluate the in vitro hMSC behavior in response to these hydrogels, looking at focal adhesion, mechanotransductive, and differentiation markers. Specific Aim 2 extends this analysis to an in vivo setting, testing the regenerative capacity of injectable microgels in rat calvarial (skull) defects. By providing a comparative analysis of bone healing with the aid of microgels of varying density and mineralization, this aim focuses on understanding the systemic host response to bioengineered grafts to be able to identify microenvironmental conditions that enhance bone regeneration. This application outlines a comprehensive training plan at a well-established institution, designed to develop my expertise in bone tissue engineering and stem cell biology, essential for becoming a craniofacial surgeon- scientist. My fellowship training will focus on gaining expertise in these areas, while developing professional skills in communication, leadership, and teaching, which are essential for my career goals of improving clinical outcomes through surgical innovation. Successful completion of this proposal will provide insights into designing scaffolds that support microenvironments conducive to accelerate differentiation, leading to improved bone regeneration outcomes. By elucidating how biomimetic environments influence differentiation and bone healing, my work aims to contribute to the development of next-generation bioengineered bone grafts, facilitating effective bone repair strategies and improving patient outcomes in craniofacial reconstruction.

NSF Awards · FY 2024 · 2024-10

Biological functional activities include intracellular functions such as transcriptional regulation, metabolism, and signaling transduction, and intercellular activities such as cell-cell interactions. With the advent of single cell multi-omics (scMulti-seq) biotechnology, researchers can study the biological functions of a complex biological system at the cellular resolution. The integrative analysis of scMulti-seq data and multiple study objects produces a wealth of rich information that enables the characterization of species or tissue specific biological functions, and at the same time, poses great challenge on how to identify and extract biologically meaningful data patterns. Though substantial amount of efforts has been made to interpret data patterns in single cell multi omics data, most of the existing methods focused on unsupervised learning in a completely data driven manner without considering the rich existing knowledge. In addition, depending on the types of biological functions, their underlying mathematical representation forms are different in scMulti-seq data. This calls for systems biology models and machine learning concepts to target true biological functions from scMulti-seq data. The first challenge to study biological functions from scMulti-seq data is to derive the data patterns that correspond to true biological functions and develop proper computational models for specific biological mechanisms and pathways. The second challenge lies in the difficulty of knowledge representation and sharing across the studies for different species, tissue types and experimental conditions. There remains an urgent need to integrate knowledge derived from disparate data sources to optimize the biological functional modeling, such that the learned knowledge could be utilized to study other biological systems or data types and promote the generation of new hypotheses. The PI’s long-term career goal is to develop mathematical formulations and computational methods to model biological functions from multi-omics data. This project will develop new mathematical models and an advanced computational framework to optimize the mining of biological functions, by integrating scMulti-seq data with context specific and general knowledge derived from independent data sets or experiments. The PI's research team will achieve the goals through the following three objectives. First, a novel subspace representation model will be developed to identify transcriptional regulation and functional gene modules. The proposed method will be empowered by a novel local low-rank matrix detection method to detect gene co regulation modules and a meta-learning framework to optimize results interpretation. Second, the PI's research team will develop a new graph neural network architecture to estimate cell-wise functional activities for flux carrying networks and a graph data clustering method to identify cell groups with varied functional states and distinct pathways. Thirdly, a knowledge graph will be constructed to represent the biological functions derived from scMulti-seq data, which enables the integration of independent knowledge derived from literature data and development of new biological hypotheses. The project is expected to deliver novel computational tools that can effectively explore biological functions from a wide range of heterogeneous datasets, and it could provide new capabilities for functional interpretation of individual data sets by maximizing the utilization of existing scMulti-seq and literature data, and reasoning of new biological hypotheses and mechanisms. Educationally, the scientific discoveries, including developed methods and biological knowledge, will be seamlessly integrated into an online educational knowledge base for large-scale public engagement, and will also lead to new project-based interdisciplinary training for high school, undergraduate and graduate students. The results of this project can be found at: https://zcslab.github.io/. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

The advancement in high throughput technologies is revolutionizing the fields of biomedical research, giving rise to large-scale patient-derived molecular datasets, including matched multi-omics data, single cell or spatially resolved -omics data, as well as longitudinal -omics data. Despite the growing trend of analyzing such complex data to further our understanding of the molecular basis in states of human disease, the inherent biological heterogeneity is challenging the conventional paradigm to treat a given diseased system as a uniform entity: patients may form different disease subtypes present with variable clinical outcomes, and cells collected from the same patient sample may display different phenotypic states. Biological and clinical interpretability in the face of the high dimensional molecular features remain to be another challenge. The proposed project will address key challenges in: 1) simultaneously detecting biologically/clinically meaningful patient/cell subgroups and extracting their unique defining genomic features; and 2) integrated learning from data of multiple modalities, with strong systematic batch effect, or collected over time. Thus, the proposed work has high potential to discover new knowledge and to induce new approaches significant to health data science research. The project will result in algorithms, such as high dimensionality reduction, clustering and data integration, that are broadly applicable across the whole of data science, to address a wide range of research and industry needs. This project proposes novel ideas of disentangled learning to simultaneously address the high dimensionality and inherent heterogeneity issues for three most popular biomedical data types: multi-omics, tissue resolved -omics, and longitudinal -omics data. The following three critical challenges are to be addressed: 1) Detecting biologically/clinically meaningful patient subgroups by leveraging multi-omics data through novel supervised clustering methods; 2) Discovering heterogeneous cell populations in noisy tissue resolved omics data and multi-task learning of multiple tissue samples through a Poisson based low dimensional embedding model; and 3) Characterizing heterogeneous disease trajectories using longitudinal and high dimensional -omics data through a fusion learning model. For all three scenarios, a common theme of disentangled learning is proposed to ensure the biological/clinical interpretability of the analysis results. The inherent heterogeneity within and across the subjects are divided to distinct subgroups or subpopulations, each of which is characterized by their unique features extracted from within a high dimensional feature space. All proposed methods are embraced with extensive utility in both academia and industry. Educationally, the proposed peer learning education module, R Shiny based tool development research, and summer workshops on data science, all targeting high school and undergraduate students, can well serve as a platform not only for inspiring and retaining students, but also training them for future STEM workforce roles. Thus, the proposed project is promising to have far-reaching educational impacts. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-09

Project Summary We will use the `incubation of craving' model to study a major challenge in treating opioid addiction, namely the persistence of vulnerability to cue-induced relapse even after long periods of abstinence. In this model, rats show progressive intensification of cue-induced drug craving in the weeks after discontinuing drug self-administration (SA); craving then plateaus at a high level before declining. We will study incubation of craving for oxycodone (Oxy), an opioid with a high abuse rate. Previously, we and others found that Ca2+-permeable AMPARs (CP- AMPAR) accumulate in synapses on nucleus accumbens (NAc) medium spiny neurons (MSN) during forced abstinence from cocaine or methamphetamine SA, strengthening these synapses and mediating expression of incubated craving. Our preliminary data show that CP-AMPARs also increase in NAc during Oxy incubation and are required for its expression, but the pathways into NAc that undergo CP-AMPAR upregulation and drive incubated Oxy seeking are unknown. To address this, we propose cell type (D1 vs D2 MSN), subregion (core vs shell), and pathway specific studies comparing saline and Oxy rats in early and late withdrawal (i.e., before and after incubation). Transgenic rats with Cre in D1 or adenosine 2a (A2a) receptor-expressing cells (D2 and A2a receptors colocalize in MSN) will be used to distinguish D1 and A2a/D2 MSN. Pathway specific studies will focus on glutamate inputs from basolateral amygdala (BLA) and paraventricular nucleus of the thalamus (PVT); both are implicated in Oxy incubation by our preliminary data. We hypothesize that cues previously paired with Oxy SA activate specific BLA- and PVT-NAc MSN pathways via CP-AMPARs and thereby drive incubated Oxy seeking. This will be tested by integrating electrophysiological and chemogenetic data across Aims. In Aim 1, we will first assess excitatory synaptic transmission, including the contribution of CP-AMPARs, in D1 and A2a MSN in NAc core and shell during Oxy incubation. Preliminary data show elevated CP-AMPARs in both D1 and A2a MSN after Oxy incubation, contrasting with D1 MSN only after cocaine or methamphetamine incubation. Then, we will use chemogenetics to determine if inhibiting D1 or A2a MSN in core or shell prevents expression of Oxy incubation. Aim 2 will assess excitatory synaptic transmission in the BLA-NAc pathway (D1/A2a MSN, core/shell) and use chemogenetics to test the role of BLA inputs in incubated Oxy seeking. In Aim 3, we will perform parallel electrophysiological and chemogenetic studies for the PVT-NAc pathway. Interestingly, prior work has shown that, in morphine-dependent rodents, CP-AMPAR upregulation in PVT-shell A2a MSN synapses mediates aversive states of opioid withdrawal. Thus, to help interpret our PVT-NAc studies and potentially set the stage for future studies on the interaction between positive and negative reinforcement in driving incubation, Aim 3 will determine if negative affective states, which contribute to relapse in opioid users, are detected alongside incubation of Oxy craving. Our studies will be the first to investigate the role of NAc synaptic plasticity in Oxy incubation and the first to study negative affect following protracted withdrawal from Oxy SA.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Healthy cerebrovascular function is required to supply adequate blood flow to metabolically active brain regions. This process occurs through neurovascular coupling (NVC), where signaling between neurons, glia, and vasculature triggers an increase in local blood flow. Impairments in vascular function are present in patients with stroke and Alzheimer's disease (AD) and are commonly associated with neurological dysfunction, hypoxia, and increased amyloid beta (Aβ) pathology. AD and ischemia are closely linked, as patients with a history of stroke have an increased chance of developing dementia, while many AD patients show indications of micro-infarcts. One possible cause for this connection could be vascular dysfunction, which occurs after ischemia and is one of the earliest complications in AD. However, the mechanisms underlying ischemia- induced vascular impairments in AD are not fully defined. In pilot studies from our lab, we find that mice exposed to a mild ischemic injury demonstrate NVC dysfunction lasting up to 8 months, with more severe deficits in a mouse model of AD overexpressing Aβ. This suggests that Aβ and ischemia may have additive effects on NVC impairment. The goal of this proposal is to study the mechanism underlying this NVC impairment and its contribution to cognitive decline and AD-related pathology. A mutual feature of AD and ischemia is oxidative stress, which leads to increased production of the vasoconstrictor, endothelin-1 (ET-1). Notably, ET-1 is elevated in patients with both AD and ischemia. Aβ has also been shown to generate reactive oxygen species that promote release of ET-1. I hypothesize that after ischemia, increase in ET-1 contributes to excess constriction, compromises NVC, and contributes to the vascular dysfunction observed in AD. I will use an innovative mouse model of mixed dementia, in which Tg2576 AD model mice receive a mild ischemic stroke in early mid-life. I will administer an inhibitor of endothelin receptor A, which is responsible for ET-1-mediated constriction, for 2 months immediately after ischemia and test whether this treatment helps retain healthy NVC and cognitive function. I will assess disease progression cross-sectionally at 2 timepoints, immediately after treatment ends and 8 months following treatment, to track pathological changes through aging. Specifically, I will investigate whether ET-1 contributes to AD-associated cognitive decline (Aim 1), vascular dysfunction (Aim 2a), histopathology (Aim 2b), and hypoxia (Aim 2c) after ischemia. I expect my findings will show that endothelin receptor A inhibition reduces behavioral deficits, NVC impairment, histopathological markers of disease, and hypoxia, thus establishing a role for ET-1 in ischemia-induced vascular dysfunction in AD. These results will contribute to our understanding of chronic vascular impairment in AD and may suggest ET-1 as a viable future therapeutic target to mitigate AD-mediated decline.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Alcohol use disorder (AUD) is a severe public health problem. Limited FDA-approved pharmacotherapies exist for AUD, and their efficacy is often insufficient. Therefore, development of new approaches for AUD treatment is necessary. A large number of preclinical studies showed that administration of oxytocin (OXT) decreases alcohol consumption in rodents. In clinical studies, intranasally administered (IN) OXT can also decrease alcohol craving, alcohol cue reactivity and measures of heavy alcohol drinking. However, some recent studies have reported lack of OXT's effects on measures of excessive alcohol drinking indicating the need for developing more nuanced treatment approaches. Understanding mechanisms underlying OXT's effect on alcohol intake may help the development of such approaches. IN-administered labelled OXT in non-human primates was distributed along the olfactory and trigeminal nerves. Therefore, exogenously administered OXT is likely to act along this route, with its potential first stage of actions in the anterior olfactory areas. Indeed, the anterior olfactory nucleus (AON) and the main olfactory bulb (MOB) express high levels of OXT receptor (OXTR) and the vasopressin receptor 1a (AVPR1a), respectively. We hypothesize, therefore, that activation of these receptors in the anterior olfactory regions results in decreased alcohol consumption. The goal of this exploratory project is to address this innovative hypothesis. This goal will be achieved in three specific aims. In Aim 1, we will examine whether chemogenetic activation of OXTR-containing AON neurons can regulate alcohol consumption in male and female mice. In Aim 2 we will examine whether chemogenetic activation of AVPR1a-containing MOB neurons can regulate alcohol consumption in male and female mice. In Aim 3 we will examine whether the anterior olfactory OXTR and AVPR1a contribute to OXT's inhibitory effects on alcohol consumption in male and female mice through a region-selective conditional deletion of OXTR. Taken together, these experiments will thoroughly test the role of anterior olfactory OXTR and AVPR1a in voluntary alcohol drinking. On one hand, they will provide a background for a thorough investigation of mechanisms involved in this role. On the other hand, they may provide a translational background for the potential of targeting the olfactory systems in the treatment of AUD.

NIH Research Projects · FY 2025 · 2024-09

Project summary Metabolic pathways are crucial for cellular energy and function. Dysregulated metabolism is a distinctive feature of various diseases, including cancer, diabetes, cardiovascular disease, inflammatory, and neurodegenerative diseases. Given its integral role in disease pathology, accurately and comprehensively characterizing metabolic alterations offers immense potential for enhancing our understanding of disease biology, improving clinical diagnostics, prevention, and management. Specifically, such characterizations can lead to: (1) a deeper understanding of metabolic variation and heterogeneity in disease tissue microenvironments; (2) the identification of novel drug targets or metabolic biomarkers for early diagnosis and treatment optimization; and (3) the development of tailored nutritional and dietary recommendations to enhance patient health quality. While significant progress has been made in studying metabolic activities across species, a pivotal gap exists. On one hand, current analyses often fail to delineate the variations and heterogeneities of metabolic activities in highly altered disease microenvironment. Existing methodologies tend to present an averaged view of heterogeneous cell populations within tissues, overlooking the intricate metabolic heterogeneity and exchanges that occur in complex tissues. This is especially concerning given that cells are known to adapt their metabolism in response to various biochemical conditions. On the other hand, compared to other areas like transcriptional regulation or immune response, there exists a marked gap in leveraging omics data to characterize metabolic variations, necessitating tailored systems biology models and tools. In this MIRA project, we aim to address these essential gaps by overcoming four challenges. First, we seek a systematic and data-driven approach to characterize metabolic landscapes in disease systems, recognizing that metabolic pathways are multifaceted and variations could span from flux to network topology. Second, we intend to harness the power of multi-omics data and extant knowledge to bridge gaps in metabolic modeling, aiming for a thorough elucidation of the metabolic fluxome and thereby achieving a holistic characterization of metabolic activities. Third, we aim to mechanistically decode the functional roles of metabolic variations in diseases, emphasizing the heterogeneity and adaptability of metabolic phenotypes. Finally, by applying our systematic research framework into our -omics testbeds covering several disease types, we aim to pinpoint metabolic abnormalities, that could aid in precision medical interventions, and diet and nutrient recommendations. Overall, our project promises to develop a suite of unparalleled computational tools: a data-driven research framework built upon a novel biophysics-informed neural network, dynamic models for in-depth metabolic analysis, cutting-edge statistical metrics, and a natural language processing tool to mine disease-specific metabolic insights from literature. This is complemented by tools for specific analytical tasks, a curated omics testbed, and a publicly accessible knowledge base. Together, these innovations promise to revolutionize our understanding of disease metabolism, with validations planned on selected systems.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The World Health Organization predicts that cancer diagnoses will increase to 22 million per year within the next two decades, with a corresponding 70% rise in cancer-related deaths. Liquid biopsy-based functional tests using blood and bone marrow will be crucial for advancing cancer precision medicine and complementing molecular genetic evaluation. Multiparameter high throughput flow and imaging platforms offer enhanced sensitivity for capture of clinically important cellular processes, and are being developed to measure therapeutic modulation of target protein signaling pathways. However, the success of these novel assays will depend on uniform standards for processing liquid biopsies across academic institutions, hospitals, and commercial entities. Currently, there is a lack of data on how pre-analytical factors, involved in the collection, and storage/retrieval of liquid specimens impact functional protein-based and live cell-dependent functional assay readouts. Therefore, pre-analytical data is critically needed to standardize workflows and support reliable clinical assay results and interpretation. Our group at the Knight Cancer Institute has collected and analyzed blood and bone marrow specimens from over 2,500 leukemia patients, resulting in the world's largest functional genomic dataset of acute myeloid leukemia (AML) patient samples. Although basic SOPs for processing and storing leukemia samples for use in functional assays have been deployed, evaluation of the impact of pre-analytical variability on assay results has not been performed. The goal of this U01 project is to characterize the pre-analytical steps involved in blood and bone marrow biopsy sample handling and storage/retrieval for functional assay reporting. The project focuses on the downstream impact of pre-analytical sample handling variability in novel, clinically relevant functional assays, namely: High Throughput-Drug Sensitivity (HT-DS), Multi-parameter High Throughput Flow (MHT-flow) and Single Cell-Multiplexed Protein Imaging (SC-MPI) assays. Our project aims to establish pre-analytical sample processing guidelines to enable maximal reproducibility for functional testing outcomes, and to evaluate the feasibility and impact of applying these guidelines in collaboration with other organizations. To that end, our proposal includes implementation and evaluation of optimized SOPs by a collaborative, interdisciplinary network that integrates clinical researchers with academic and private sector scientists. Overall, the goal is to establish pre-analytical workflow guidelines that optimize phenotypic cell identity and protein-based readouts for functional platform tests that are currently being used in drug therapeutic development and precision medicine clinical trials. The results of this work will help establish well-defined workflows critical for the successful and uniform adoption of functional platform testing across national clinical sites, as well as industry, and will broadly impact the growing number of new functional tests in development and clinical translation in areas such as immuno-oncology, early detection, and measurable residual disease.