Oregon Health & Science University

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Acute kidney injury (AKI), defined by sudden onset renal cell injury and functional impairment, occurs in up to 15% of hospitalizations and 60% of critically ill patients. AKI also damages other organs, including the brain, lungs, and cardiovascular system, and can become lifelong chronic kidney disease (CKD). There is currently only one clinically approved treatment for AKI: aggressive fluid resuscitation immediately following injury. Pregnancy causes stress on maternal organs to grow a fetus, including providing blood supply. The kidney is critical to this process as it controls vascular tone and blood pressure through the renin-angiotensin system. Available data suggest women with recovered AKI are at risk for adverse maternal and fetal outcomes, including preterm birth and fetal growth restriction, which are linked to later disease in the offspring; this underlies the importance of a mechanistic understanding of this long-term outcome of AKI. As people of childbearing age experience a lifelong risk of reproductive and renal complications, the increase in AKI in this population mandates investigation. We hypothesize that recovered rhabdomyolysis- induced AKI (RIAKI) causes quantifiable intrarenal renin-angiotensin system (RAS) alterations in pregnancy, leading to gestational complications, placental insufficiency, and later maternal renal dysfunction. This hypothesis will be tested using an in vivo mouse model of RIAKI, a form of AKI observed in young people from muscle injury sustained during exercise, combat, and accidents; therefore, this is a relevant model to study the long-term impact of recovered AKI on people of childbearing age. Aim 1 will determine whether maternal recovered RIAKI alone is sufficient to result in dysfunctional pregnancy—versus including paternal and fetal effects in the model—by natural breeding and implanting embryos from non-procedure mice into RIAKI dams and comparing maternal outcomes to shams. We will also test a drug, cilastatin, administered at injury to determine if post-AKI pregnancy complications are improved. In Aim 2, the intra-renal mechanisms in recovered RIAKI dams regulating vascular control in pregnancy will be assessed for postpartum maternal outcomes by modifying renal ACE2, a critical component of the renal renin-angiotensin system. In Aim 3, maternal urinary biomarkers will be identified at clinically relevant postpartum time points to diagnose maternal renal disease early and provide new therapeutic targets. This career development proposal contains a comprehensive training plan to strengthen existing scientific competency and develop career-long collaborations. The K01 will apply existing reproductive expertise to a new question with significant translational impact, supporting the applicant in becoming an independent investigator of the links between renal, reproductive, and developmental pathology. Ultimately, these studies are designed to understand the risks of AKI on reproductive outcomes and develop novel interventional strategies to prevent long-term disease in parents and offspring.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Amyotrophic Lateral Sclerosis (ALS) is the third most common neurodegenerative disease, with no cure and limited treatment options. While motor neurons are primarily affected, non-neuronal cells, particularly myeloid cells (microglia and peripheral macrophages), significantly influence disease progression. Our preliminary studies identified α5 integrin as a novel molecular switch that emerges in myeloid cells during ALS progression and correlates with inflammatory states in both familial and sporadic ALS patients. Importantly, blocking α5 integrin significantly extends survival in ALS mouse models. This proposal aims to define the mechanistic role of α5 integrin in ALS pathogenesis through two specific aims: 1) Define the cell type-specific contributions of α5 integrin in ALS pathogenesis using conditional knockout models to selectively delete α5 integrin in microglia and/or peripheral macrophages, and 2) Elucidate how α5 integrin regulates microglial function in ALS pathology using human iPSC-derived cellular systems. We hypothesize that α5 integrin functions as a critical molecular switch driving the transition of myeloid cells from homeostatic to disease-associated microglia (DAM) states in ALS. By combining genetic models with human iPSC-derived cellular systems, we will determine how α5 integrin influences microglial migration, phagocytosis, and interactions with motor neurons in both healthy and ALS contexts. This study represents the first comprehensive investigation of α5 integrin's role in myeloid cell function in ALS. Our preliminary data suggests that targeting α5 integrin represents a novel therapeutic strategy to modulate and slow disease progression. By elucidating the molecular mechanisms governing myeloid cell contributions to ALS pathology, we will pave the way for more effective immunomodulatory treatments for this devastating disease.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Cancer is the second leading cause of death in the US. Guideline concordant screening reduces cancer mortality, minimizes morbidity, and facilitates timely treatment. However, many eligible adults are not up to date for the multiple cancer screenings recommended at the A and B level by the US Preventive Services Task Force (USPSTF): 86% lung, 20% breast, 36% colorectal, and 26% cervical. Moreover, screening rates could be improved even further for some populations (e.g., rural, low income or uninsured). Population outreach interventions using text, mailing, and/or patient navigation increase screening. Yet, most outreach studies address a single cancer rather than all recommended by the USPSTF in alignment with whole person care and clinician preferences. The Bundled Outreach of Multiple Cancer Screenings for Under-screened Populations (BUNDLE) study will adapt our previously tested multicomponent outreach interventions for single cancer screenings to include multiple cancer screenings (the BUNDLE intervention). BUNDLE is a collaboration between the Oregon Rural Practice-based Research Network and the Knight Cancer Institute at Oregon Health & Science University, and the University of North Carolina Comprehensive Cancer Center. Activities will engage at least 18 unique primary care clinics and reach more than 1600 patients in Oregon and North Carolina. In the 2-year UG3 Research Planning Phase we will: 1) adapt our intervention process and materials via user centered design; 2) pilot and assess intervention acceptability, feasibility, and preliminary effectiveness; and 3) finalize clinic recruitment and prepare for the trial. In the 4-year UH3 Research Execution Phase we will: 4) implement and evaluate reach and effectiveness of the BUNDLE intervention compared to usual care on change in cancer screening in a pragmatic, two-arm, wait-list control, cluster randomized trial; 5) assess patient and clinic experience and cost-effectiveness (cost per screening) of the BUNDLE intervention; and 6) explore how multilevel factors (patient, clinic, community) explain cancer screening completion using configurational analysis. Our primary outcome is completion of any USPSTF- recommended screening test (colorectal, breast, cervical, lung) with a 10% or more hypothesized increase for intervention versus control patients. Secondary outcomes are reach, completion of two or more cancer screenings, completion of all eligible cancer screenings, patient and clinic experience, cost-effectiveness, and multilevel screening factors. More than 31 clinic and health system leaders providing primary care for populations with lower rates of cancer screening in Oregon and North Carolina are eager to participate in BUNDLE. Findings will advance the science and practice of population outreach interventions focused on multiple cancer screening. Bundled outreach interventions could enable primary care clinics to pool and focus limited resources in efficient ways.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY ATP-sensitive potassium (KATP) channels, gated by intracellular nucleotides ATP and ADP, couple cell energetics with membrane excitability to govern a wide range of physiological processes vital to energy homeostasis. KATP channels are unique hetero-octameric membrane protein complexes of four inward rectifier K+ channel (Kir6.1 or Kir6.2) subunits and four sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Various Kir6.x/SURx combinations generate KATP channel isoforms with distinct tissue distribution, nucleotide sensitivity, and pharmacology. The most prominent KATP channels are those of Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.1/SUR2B combinations, representing the major pancreatic, cardiac, and vascular smooth muscle isoforms, respectively. Mutations in genes encoding the various KATP channel proteins result in endocrine, cardiovascular, muscular and neuronal disorders, including congenital hyperinsulinism, neonatal diabetes, DEND syndrome, and Cantύ syndrome. The long-term goal of our research is to understand the structure-function relationship of KATP channel isoforms in health and disease and develop mechanism-based, isoform-specific therapies for disease caused by KATP channel dysfunction. A key barrier to progress has been a lack of detailed structural knowledge of the channels and their interactions with physiological and pharmacological ligands. In 2016, my lab broke this barrier by reporting the first high-resolution structure of the SUR1/Kir6.2 channel using single-particle cryo-electron microscopy (cryo-EM). We have since published a series of KATP channel structures bound to various ligands in different gated conformations at near atomic resolutions, which have significantly advanced our understanding of how the SUR and Kir6 subunits assemble and interact with each other and how they interact with ligands to control activity. Most exciting, we have begun to harness the structural knowledge to discover new compounds that modulate KATP channel assembly and gating. Despite the progress, significant knowledge gaps remain. In this new MIRA application, we seek to build on the tools and knowledge we have amassed and continue tackling the most pressing and challenging questions in the field using a multipronged approach that combines structural biology, computational biology, chemical biology, and electrophysiology. The three research directions we will focus on are: (1) solving additional cryoEM structures of pancreatic, cardiac, and vascular channels to obtain a comprehensive suite of channel structures in closed and open conformations, (2) elucidating the functional relevance of structural observations, especially focusing on lipid interactions and the role of intrinsically disordered regions, and (3) expanding KATP pharmacology by characterizing KATP structures bound to existing and novel drugs with a range of affinities and isoform-selectivity. By comparing and contrasting related KATP channel complexes we expect to uncover the general design principles that allow KATP channels to operate as ATP/ADP sensors and the specific mechanisms that underlie the unique gating properties and pharmacology of different KATP channel isoforms, which will have major and lasting positive impact on the KATP research field.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Leishmania parasites cause a suite of devastating Neglected Tropical Diseases that afflict as many as one million people per year. At least 20,000 are killed each year by the deadly visceral form of the disease, which is caused by Leishmania donovani. The signal transduction pathways used by these parasites to sense and respond to their host environments are poorly understood. Identification of signaling pathways essential for parasite survival may lead to new targets for antileishmanial drug development. Genetic screens targeting signaling pathways offer a powerful means of discovering genes encoding important signaling proteins. A recent CRISPR/Cas9-mediated knockout screen targeting 204 protein kinases found 44 essential kinases in Leishmania mexicana. Using barcode sequencing (Bar-seq) technology, this study also identified more than 50 kinases that were involved in progression through at least one lifecycle stage, both in cell culture, and in sand fly and mouse models of infection. However, these Loss-of-Function (LoF) knockout screens are tedious and expensive to implement, making it challenging to apply these methods to the hundreds of additional signaling proteins with unknown roles in Leishmania survival. We propose to take a Gain-of-Function (GoF) genetic screening approach to understand Leishmania signal transduction. Like LoF gene knockouts, GoF approaches that express proteins at higher levels than normal (i.e., overexpression) can cause deleterious effects on cell fitness that reveal important pathways and protein functions. We have generated a library of 440 known or predicted L. donovani signaling proteins, cloned into novel barcoded inducible expression vectors developed in our lab. This signaling library will be transfected into L. donovani and then used to identify signaling proteins that cause fitness defects upon induction of overexpression via Bar-seq. We will conduct GoF overexpression screens to discover signaling proteins and pathways critical for progression through in vitro (Aim 1) and in vivo (Aim 2) lifecycle stages. Many of the signaling proteins encoded in our library have not been studied before. Therefore, we anticipate we will uncover previously unknown roles for many signaling proteins in Leishmania lifecycle progression. Our GoF signaling library overexpression platform will be simpler to implement and easier to share with other researchers than LoF knockout libraries. The signaling library can be applied to identify signaling proteins critical for surviving any growth condition, and can be readily moved into other Leishmania species. We predict that the signaling library and the information gleaned from the proposed overexpression screens will serve as valuable resources for the Leishmania community.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Ovarian cancer is the most lethal gynecological malignancy, with most patients succumbing to recurrent disease due to resistance to available treatments. The primary treatment regimen—surgery followed by platinum- or taxane-based chemotherapy—offers limited long-term success, as 85-90% of women diagnosed with late-stage disease will recur post adjuvant combination chemotherapy, a highly undesirable outcome largely driven by the development of treatment resistance. Once ovarian cancer recurs, available treatments are palliative. The lack of treatment options for these patients is a critical unmet need in the clinic; we propose this need can be addressed with a novel therapeutic approach that directly addresses treatment resistance in recurrent patients. One such approach is to therapeutically inhibit Y-Box Binding Protein 1 (YB-1), a stress-responsive, multifunctional protein implicated in ovarian cancer progression and treatment resistance. Beyond its routine cellular roles in RNA stability, splicing, translation, cell proliferation, and DNA damage repair, YB-1 overexpression in ovarian cancer is associated with faster progression, increased metastasis, and higher mortality. This association with poor prognosis may be driven, in part, by YB-1’s contributions to treatment resistance, as YB-1 is associated with ovarian cancer resistance to cisplatin and paclitaxel. This dual role in ovarian cancer progression and treatment resistance makes YB-1 a compelling therapeutic target. We propose to therapeutically inhibit YB-1 using SU056, our novel azapodophyllotoxin that is, to our knowledge, the only small molecule inhibitor of YB-1. SU056 binds to YB-1, inducing ovarian cancer cell cycle arrest, apoptosis, and inhibition of ovarian cancer cell proliferation and migration. Importantly, both in vitro and in vivo, ovarian cancer cells are sensitive to SU056 single agent therapy and sensitized to paclitaxel in the presence of SU056. Our preliminary data suggests that SU056 decreases expression of the multi-drug efflux pump, MDR1, thereby reducing paclitaxel efflux and enhancing chemotherapy sensitivity. Because MDR1 upregulation is associated with treatment resistance against chemotherapies, this data suggests one mechanism by which SU056 could sensitize cells to chemotherapies commonly used to treat ovarian cancer. Building on this preliminary data, our central hypotheses are that YB-1 inhibition by SU056 effectively restrains tumor growth in chemoresistant ovarian cancer models, both as a single agent therapy and in combination with standard chemotherapies. Our goals are to 1) Elucidate mechanisms of SU056 single-agent activity; 2) Identify pathways of chemoresistance targeted by SU056; and 3) Evaluate SU056’s synergy with existing ovarian cancer treatments. Given the dismal prognosis for recurrent ovarian cancer, this research is significant because inhibiting YB-1 represents a highly promising therapeutic strategy, and through YB-1 inhibition, SU056 has high potential to increase sensitivity to available therapies, overcome treatment resistance, and improve outcomes for ovarian cancer patients.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Cannabis is now the most commonly used federally illegal drug during pregnancy, where it is often used to alleviate symptoms of nausea, insomnia, pain and stress. The high prevalence of use is partly because safety data is substantially lacking, especially on the developing fetal brain. Thus, individuals continue to use cannabis when trying to conceive, or even during pregnancy, because it is perceived as harmless. The available studies are often limited by self-reported cannabis intake and other confounding variables, including polysubstance use, but suggest that prenatal cannabis use is associated with an increased risk of offspring neurodevelopmental deficits. Babies prenatally exposed to cannabis display an exaggerated response to stimuli, sleep disruption, and a high-pitched cry, indicative of adverse neurological development. Our group also has recent preliminary data that shows that chronic prenatal 9-tetrahydrocannabinol (THC, the main psychoactive component of cannabis) exposure in pregnant rhesus macaques negatively affects offspring brain development, including decreased brain volume, and transcriptional and epigenetic changes. The central hypothesis is that maternal prenatal cannabis use adversely impacts offspring neurodevelopment and emotional behavior. At present, there is insufficient evidence to establish a direct association between maternal cannabis use and later child outcomes. This gap in knowledge is due to the lack of relevant preclinical models that have strong translation to human health. Brain development is different in rodents than primates, including cortical expansion, neurogenesis, and brain size. We propose to address this knowledge gap by leveraging our first-in-kind translational rhesus macaque model of chronic edible THC use to fundamentally understand how maternal cannabis use shapes offspring brain and behavioral development. Edibles are the second most common mode of cannabis delivery amongst pregnant individuals, and allow rigor and reproducibility in dosing. The objective of this study is to examine the impact of chronic (e.g., daily use) maternal prenatal THC use on neonatal and infant neurodevelopment and behavior. This comprehensive study will bridge the gap in knowledge regarding how maternal cannabis use impacts offspring health. The successful completion of our study will result in: 1) new insights into the direct impact of chronic maternal THC use during pregnancy on offspring neurodevelopment, sensorimotor development and emotional behavior, 2) defining the effect of in utero THC exposure on the infant brain epigenome and transcriptome, and cannabinoid receptor expression and localization, and 3) the creation of a publicly-available non-human primate tissue bank of comprehensive biological samples and offspring tissues (control and THC- exposed) that can be used as a reference for other environmental exposures and can be accessed by other substance use researchers. Results from our proposed work will guide patient counseling, be used for harm reduction, and inform future studies focused on maternal cannabis use.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Periodontitis (PD) is an oral inƲammatory disease caused by the dysbiosis of the oral microbiota. The existing diagnostic and treatment methods do not offer satisfactory outcomes and do not present the active status of the disease. The ideal platform for the management of PD is to target the multiple factors (bacteria, biofllm, inƲammatory molecules), simultaneously executing real-time analysis of the disease. This simultaneous diagnosis and therapy can be performed by a theranostic (therapy + diagnosis) biomaterial, and our long-term goal is to develop and validate multifunctional theranostic platforms for oral inƲammatory diseases. The present study focuses on the synthesis and validation of granular hydrogel platforms for the theranostic management of periodontitis. Granular hydrogels (set of tightly packed microgels) are advantageous when compared to conventional bulk hydrogels as they can act as heterogenous carriers for the encapsulation/surface functionalization of an array of agents. In the present work we are proposing the synthesis of granular hydrogels made up of thiolated chitosan (ThCS) microgels encapsulating therapeutic agents or surface functionalized with diagnostic molecules. In summary, the proposed speciflc aims are to synthesis, characterize and validate (1) Diagnostic granular hydrogel, comprised of ThCS microgels functionalized with MMP -2 and -9 susceptible MMPSense™ 750 Ʋuoropeptide for the precise diagnosis of PD; (2) Therapeutic granular hydrogel, comprised of ThCS microgels encapsulated with therapeutic agents thymol and Zinc substituted hydroxyapatite for the multimodal therapy of PD and (3)Theranostic granular hydrogels comprised on ThCS microgels either encapsulating the therapeutic agents or functionalized with diagnostic peptide capable of performing precise diagnosis and multimodal therapy of PD. The prepared granular hydrogels will be characterized (morphology, rheology, in vitro degradation, drug release, sensitivity & speciflcity of the Ʋuoropeptide) before diagnostic / therapeutic validation. The central hypothesis is that the theranostic granular hydrogel can perform precise diagnosis of PD as MMP- 2 & -9 are expressed actively in the periodontal pocket which will cleave the MMPSense™ 750 Ʋuoropeptide resulting in infra-red Ʋuorescence, while performing multimodal therapy mediated by thymol (antibacterial & anti-inƲammatory) and zinc substituted hydroxyapatite (antimicrobial and anti-biofllm). The skill set to accomplish this proposed project will be acquired during the K99 phase with the support of my mentoring team (Drs. Ana Fugolin, Jack Ferracane, Phillip Marucha and Luiz Bertassoni). The combination of new techniques and career development trainings acquired during the K99 mentored phase, my prior expertise in biomaterials synthesis and characterization will lay foundation of my independent career focused on theranostic biomaterials. Additionally, this proposal will be a proof-of-concept for understanding how theranostic biomaterials can be utilized in dentistry which was previously conflned to the fleld of oncology.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Lung metastasis is the primary cause of death in osteosarcoma (OSA) patients, with 5-year survival rates of approximately 20% using current treatments. Our recent findings highlight the need to target both tumor and microenvironment-derived factors, revealing that resident lung and immune cells released growth factors that activated tumor survival pathways upon metastasis, particularly prosurvival gene, MCL1. Inhibiting MCL1, especially when combined with cyclophosphamide, showed promising results in our preclinical model studies, eradicating metastatic lesions in some cases. However, several questions remain as to the specificity of MCL1 as a target and the feasibility of targeting this prosurvival pathway for osteosarcoma treatment. To this end, in Aim 1, we will deploy a novel bioengineered bone and lung model for real-time cell tracking to definitively establish the role of MCL1 in lung metastasis and validate these findings in vivo. We will then identify MCL1 inhibitors most able to eliminate metastases in our engineered model, in vivo, and test their safety in preclinical models. In Aim 2, we will identify mechanisms linking microenvironment-driven osteosarcoma signaling and MCL1 regulation in the lung. By using ex vivo and in vivo approaches, we will pinpoint critical ligand-receptor interactions and test receptor-level inhibitors, aimed at blocking the effects, to reduce metastatic osteosarcoma MCL1 protein levels. Promising inhibitors will then be evaluated for their effectiveness in combination with low- dose MCL1 inhibitors to eliminate lung metastasis and safety in preclinical models. Overall, this proposal aims to fully validate the potential of MCL1 inhibitors and explore combinatorial therapies to enhance efficacy and reduce toxicity, using innovative tumor-host interaction models, paving the way for future clinical trials.

NIH Research Projects · FY 2026 · 2026-03

SUMMARY Prostate cancer exhibits evident predilection for bone metastasis, occurring in over 80% of advanced cases and causing serious skeletal complications. While organ-on-a-chip platforms have advanced metastasis research, existing microphysiologic bone metastasis models fail to recapitulate critical microenvironmental features, particularly functional vascular networks, innervation and controlled nanoscale mineralization around cells, all which govern metastatic colonization. Building on the seed (tumor cells) and soil (metastatic microenvironment) paradigm of cancer metastasis, we developed an innovative bone metastasis-on-a-chip platform incorporating a mineralized, osteocyte-embedded bone matrix supporting active osteoclast/osteoblast remodeling, perfusable pericyte-supported vasculature to study extravasation dynamics, and integrated neural networks to promote tumor-nerve crosstalk. Our preliminary data reveal that circulating tumor cells (CTCs) experience mechanical nuclear deformation during bone vascular transit, a distinctive phenomenon of metastasis that is absent in other vascular models, suggesting that bone-specific vascular forces may prime metastatic adaptation. Simultaneously, we discovered that neural components actively upregulate pro-metastatic molecular profiles in tumor cells while undergoing tumor-induced remodeling. Here, in Aim 1, we will leverage this platform to interpret how bone-specific vascular mechanics, including pericyte-stabilized endothelial interactions and cellular deformation, orchestrate CTC extravasation and subsequent osteolytic destruction, combining high-resolution live imaging with single- cell analyses of deformation-induced genomic/epigenetic changes. In Aim 2, we will elucidate neural contributions to metastatic niche formation, testing how bidirectional tumor-nerve signaling accelerates bone colonization and bone resorption/destruction. This work addresses two understudied yet pivotal aspects of the metastatic cascade: the deformation and genomic instability of CTC fate during vascular transit, and the neural contribution to of the "vicious cycle" of prostate cancer metastasis into bone. By integrating vascular, neural, and osseous components into a single physiologically relevant, all human platform, we will establish the first model capable of emulating the tripartite interplay driving prostate cancer's bone tropism. The resulting insights and tools will not only reveal new therapeutic targets for bone metastasis but also provide a high-fidelity platform for studying microenvironmental regulation of metastasis across cancer types.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Neuromodulation imposes powerful control over brain function by dynamically adjusting the gain and plasticity of brain circuits. Defects in neuromodulation are associated with many neurodegenerative and neuropsychiatric diseases. It is increasingly appreciated that an in-depth understanding of neuromodulation would involve visualizing these events during animal behavior. Currently, in vivo interrogation of extracellular neuromodulator releases has become possible thanks to the development of neuromodulator sensors. However, neuromodulators exert their functions by regulating intracellular signaling events, such as those mediated by cAMP and protein kinase A (PKA), in a cell-specific manner: the same neuromodulator may trigger distinct signaling events via different receptors in different cell types. Cell-specific monitoring of neuromodulatory signaling is needed. To date, cAMP and PKA sensors have been developed and started to allow initial in vivo imaging applications. However, the signal remains low, hampering the simultaneous measurements of a large number of cells or the visualization events confined in subcellular compartments. Here, we propose to optimize a FRET-based multi-fluorophore sensor for PKA activity and a single-fluorophore sensor for cAMP that provide complementary information. We will prioritize developing sensors compatible with fluorescence lifetime imaging, which is increasingly recognized to provide unparalleled advantages for imaging signaling events in vivo. We will employ structure-guided molecular dynamic analyses to identify critical positions within each sensor and use a modern high-throughput platform to screen for effective variants. We will benchmark the new variants against previous sensors. Leading candidates will be systematically characterized, benchmarked against current best sensors, and validated in vitro and in vivo. This proposal harnesses the complementary expertise from individual team members, including experimental structural biology, molecular dynamics, sensor development and characterization, and in vivo two-photon lifetime imaging. Successful tools will be used to generate adeno-associated viruses (AAVs) and other cell type-specific expression vehicles for easy use and dissemination to the broader research community. If successful, our proposed study will propel the ability to visualize cAMP/PKA signaling activities in vivo with previously unattained spatial and temporal resolution for mechanistic studies of brain function and dysfunction. This ability to monitor neuromodulatory signaling will complement the measurements of extracellular neuromodulators and neuronal electric activities to enhance our understanding of brain function underlying animal behavior.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY The human serotonin transporter (hSERT) plays a critical role in regulating serotonin (5-HT) signaling across nearly all major systems in the body. Dysregulation of hSERT is linked to numerous psychiatric and gastrointestinal disorders, making hSERT a primary target for clinical therapeutics including selective serotonin reuptake inhibitors (SSRIs). While the core ion-coupled transport cycle of hSERT is well characterized, the allosteric mechanisms that fine-tune its activity to meet diverse physiological demands remain poorly understood. This proposal aims to define the structural mechanisms by which 5-HT and the microbial metabolite butyrate allosterically shape hSERT’s conformational landscape to modulate its function. Aim 1 will leverage innovative cryo-EM approaches capable of resolving the full range of conformational states that define hSERT’s transport cycle, enabling the distinct structural effects of ligand binding at the central (S1) and allosteric (S2) substrate- binding sites to be isolated and characterized. These conformational changes will be directly linked to transport activity using complementary 5-HT uptake and electrophysiological assays. Aim 2 will expand our understanding of hSERT allosteric regulation by identifying the binding site of butyrate, characterizing its effects on hSERT’s conformational equilibrium, and determining its impact on transport activity. The training plan outlined in this fellowship is designed to strengthen technical and conceptual expertise in membrane protein biochemistry, single-particle cryo-EM, and electrophysiology. Mentorship and training from Dr. Eric Gouaux, an internationally recognized leader in membrane protein structural biology, and Dr. Michael Kavanaugh, an expert in transporter electrophysiology, will ensure the successful completion of the proposed aims. Together, these studies will advance the fundamental understanding of hSERT regulation and contribute to a broader framework for understanding allosteric modulation in neurotransmitter transporters, informing the development of innovative therapeutic strategies for disorders involving transporter dysfunction.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY In the auditory system, after sound is transduced by hair cells, the signal flows through a well-defined ascending route: cochlear nerve; cochlear nucleus; superior olivary complex (SOC); and inferior colliculus, before reaching higher processing areas. In mammals, signals from both ears must reach neurons in the SOC with high temporal precision so that binaural sound stimuli can be processed. An inability to encode and process accurately sound cues from both ears, especially in noisy environments, configures several forms of hearing loss (HL), a feature commonly associated with aging. Hearing impairment contributes to social isolation by burdening the individual with an exacerbated focus on processing speech. Social isolation reduces exposure to cognitive stimulation and may aggravate or even lead to instances of cognitive decline in those prone to it. Alzheimer’s disease (AD) is a progressively deteriorating condition that affects cognition globally. Importantly, AD is often associated with abnormal binaural hearing, especially in noisy environments. Thus, detecting early-onset deficits in binaural hearing and pairing it with AD likelihood is invaluable for guaranteeing quality of life for those at risk of eventually developing AD. This proposal aims to determine how auditory signal propagation is affected in different stages of AD progression associated with or without early HL. We will perform these studies using mouse models that develop early-onset AD (5xFAD) and HL (C57) to determine the changes in neuronal excitability and synaptic strength within the auditory brainstem that arise from the interaction of these conditions. We will focus on two specialized synapses in the auditory brainstem: the large calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) and the small bouton-type glycinergic and glutamatergic synapses of the lateral superior olive (LSO). These synapses are pivotal for the auditory brainstem circuits that compute sound source localization through binaural cues. In addition, we will study the binaural processing functionality using auditory brainstem recordings (ABRs) and behavioral studies such as the acoustic startle response (ASR). Preliminary data from our lab supports the hypothesis that healthy hearing delays AD progression at synaptic and behavioral levels. To further understand how this interaction may affect AD progression, we will use in vitro and in vivo approaches to 1) determine the underlying synaptic and neuronal changes in SOC circuits through single-cell patch clamp electrophysiology; 2) investigate non-invasively how sound processing is affected when AD and HL are associated, aiming for an early tool for AD forecasting; 3) correlate cellular, neuronal population and behavioral changes with aging in males and females. These results will provide novel insights into underlying functional deficits in AD development and its correlation with HL in different adult populations. The proposed studies will thus significantly enhance our fundamental understanding of AD and HL interactions in the mammalian brain.

NIH Research Projects · FY 2026 · 2026-02

The rapid shift in public perception of psychedelics, coupled with the expansion of their use and policy reform across the United States, has created a unique opportunity to assess the real- world impacts of psychedelic use. Over 7,000 people in Oregon have received legal, supervised psilocybin experiences. Similar services are set to begin in Colorado in 2025, and nine other states are currently considering psychedelic services legislation. Although early phase trials suggest psilocybin may be safe and effective for treating some mental health and substance use disorders (e.g., tobacco use), it is not known whether these effects extend to community- based settings with less standardized screening and counseling support. There is an urgent need to assess the safety of these programs and their impact on substance use, before more voters and policymakers are asked to consider their merits and drawbacks. The Psilocybin Research and Implementation study for Substance use and Mental health (PRISM) study is designed to fill this gap by enrolling a cohort of individuals who use substances and receive Oregon’s state-regulated psilocybin services and comparing them to a group of people who would access these services, if they were available. Using 12 months of rigorous longitudinal surveys and qualitative interviews, PRISM will detect potential safety risks and benefits of regulated psilocybin services and identify specific substances and subpopulations that may be responsive to psilocybin’s effects. The study has three Aims: 1) Assess the impact of state- regulated psilocybin services on safety events in people who use substances, 2) Assess the impact of state-regulated psilocybin services on substance use, and 3) Elicit stakeholder views of the impact of state-regulated psilocybin services on long-term safety and changes in substance use. The PRISM study seeks to generate rigorous real-world evidence that can effectively guide state and federal decision-making. The timing of this work is critical, given the rapid expansion of psychedelic policy reform across the United States. The findings will help shape policies that maximize potential benefits of psilocybin services while minimizing risks, offering a scientifically grounded framework for public health strategies, harm reduction efforts, and future psychedelic regulations.

NIH Research Projects · FY 2026 · 2026-02

Project Summary In the United States, a person is more likely to be infected by a non-tuberculous mycobacteria (NTM) than Mycobacterium tuberculosis (Mtb). Most NTM pulmonary infections are caused by one of two species: Mycobacterium avium or Mycobacterium abscessus (Mab). Of the two, infections with Mab are the most difficult to cure and, consequently, lead to highest rate of mortality among NTM diseases. Mab is intrinsically resistant to most antibiotics and there are no FDA approved drugs to treat this disease. Further challenges come from the pronounced strain-to-strain variability in drug response. New treatment strategies for people infected with Mab are urgently needed. There is emerging evidence that Mab infections can be cured through treatment regimens that include two β-lactam antibiotics at once, termed “dual β-lactam therapy”. Currently there is widespread hesitancy by clinicians to using dual β-lactam therapy for NTMs because such treatment conflicts with decades of guidelines for using β-lactams to treat other bacterial infections. However, those guidelines do not consider the complement of enzyme targets for these drugs that are definitively different in mycobacterial pathogens. For this R21 project, we propose to collect comprehensive data describing the underlying mechanism of action for dual β-lactams in Mab, which is currently unknown. This direct evidence is both urgent and necessary to clearly describe the mechanistic basis of the synergistic activity of dual β-lactams treatment. It is additionally needed to update guidelines for using this novel and effective therapeutic approach to treat NTM infections in patients. We hypothesize that dual β-lactam treatment is more effective than a single drug alone against Mab because the combination of two drugs halts the catalytic activity for a broad set of enzymes used for cell wall biosynthesis. In Mab, this most likely includes more than just the penicillin-binding proteins (PBPs) because L,D-transpeptidases (LDTs), a distinct enzyme class, make the 33 cross-links that predominate in the mycobacterial cell wall. We predict that some dual β-lactams combine to comprehensively inhibit both PBPs and LDTs. We will test our hypothesis through the application of novel chemical probes, called activity-based probes (ABPs). These ABPs are designed to irreversibly label enzyme targets of β-lactams, including mycobacterial PBPs, LDTs, and β-lactamases. We propose to complete two Aims: Aim 1. To identify β-lactam enzyme targets associated with Mab disease. Aim 2. To identify Mab enzymes inhibited potently by dual β-lactam treatment. Successful completion of this R21 project will provide ground-breaking insights into the most efficacious combinations of β-lactam drugs against Mab, information that can be immediately used to design clinical trials and, ultimately, improve treatment regimens for patients infected with Mab and other NTMs.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Millions of elderly individuals suffer from visual impairment due to dry age-related macular degeneration (AMD), for which effective treatments are limited. In advanced stages of dry AMD, the gradual loss of retinal pigment epithelial (RPE) cells leads to the death of overlying photoreceptors, causing progressive vision loss and eventual blindness. Transplantation of healthy RPE to replace lost/diseased RPE cells have shown in rodent studies to rescue rod and cone photoreceptors, improve retinal electrophysiological responses, and enhance visual thresholds over extended periods. However, these studies have used xenogeneic (across species) cell transplants, which require immune suppression (IS) to prevent the host’s immune system from rejecting the transplanted cells. Similarly, allogeneic (same species) RPE cell transplants in non-immune suppressed models, including pigs and nonhuman primates, are typically rejected within three weeks. Although IS appears currently necessary and sufficient to protect transplanted cells, it raises significant safety concerns, especially for elderly AMD patients who may experience toxic side effects from long-term or indefinite IS use. Additionally, IS introduces challenges such as patient compliance and the risk of rejection with suboptimal dosages. Current Phase I/II clinical trials using allogeneic RPE cells combine multiple IS medications to prevent rejection, but the majority of adverse effects stem from the IS regimen rather than the cell therapy itself. To address the complications of IS, the NIH has initiated an autologous RPE cell trial, despite the high logistical and cost barriers to broad implementation. In contrast, our approach focuses on developing a scalable allogeneic cell-based therapy that can avoid immune rejection, providing greater access, efficiency, and lower costs. We have demonstrated feasibility of this approach in multiple settings including short-term RPE cell transplants in the eye in non-immune suppressed NHPs. In the proposed studies, we will generate multiple lines of allogeneic induced pluripotent stem cells (iPSCs) from nonhuman primates (NHPs) and engineer them to lack expression of class I and II major histocompatibility complexes and to overexpress the “don’t eat me” signal, CD47. We will then optimize the differentiation of these modified iPSCs into RPE cells for transplantation studies in both normal and diseased NHP retinas. Transplantation studies will include short and long-term survival and in diseased retinal conditions to replicate acute version chronic rejection in normal and diseased retinal environments. Finally, we will optimize the use of a safety switch to enable selective removal of cells in the subretinal space should that ever be necessary. These studies will demonstrate the potential of gene-modified RPE cells to evade immune rejection while maintaining a high safety profile and will help identify factors in retinal disease environments that may affect the survival of transplanted RPE cells. Successful completion of these aims will lay the groundwork for translating these studies toward clinical application.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Type I interferon (IFN) is the first line of defense in innate antiviral immunity, orchestrating transcriptional and metabolic responses that restrict viral replication. While IFN signaling is known to modulate sterol and glycerolipid pathways, its impact on sphingolipids (SPLs)—a class of bioactive lipids involved in immune signaling and cell stress responses—remains poorly understood. Mounting evidence suggests that infections by RNA viruses, including flaviviruses and coronaviruses, induce the accumulation of ceramide (Cer), but whether this promotes viral replication or enhances antiviral defenses is unclear. Our preliminary studies show that Zika virus (ZIKV) triggers overall changes in SPL composition and relies on Cer biosynthesis for successful infection. However, other studies implicate Cer in restricting viral replication and promoting cell survival, raising the possibility that these lipids are upregulated by the host response rather than the virus. The central goal of this proposal is to uncover how type I IFN affects SPL metabolism and to determine whether these lipids, in turn, control the IFN response and infection outcomes. We hypothesize that SPLs, particularly Cer, play a dual role in infection and immunity. Viruses may induce Cer to suppress innate immune responses, including IFN production, as suggested by the known roles of Cer in modulating host signaling pathways. However, we also propose that IFN itself alters SPL metabolism, as it does with other lipid classes, and that these IFN-induced lipid changes may contribute to antiviral defense. To disentangle these possibilities, we will use a combination of untargeted lipidomics, innovative SPL probes, CRISPR gene editing, and organelle-targeted lipid perturbation to systematically determine the causes and consequences of SPL dysregulation in infection. Aim 1 will define how IFN-β alters SPL content and distribution in infected and uninfected cells. In doing so, we will generate the first comprehensive map of IFN-driven changes in the cellular lipidome—including SPLs—across multiple cell types, providing a foundational resource for the broader virology and immunometabolism communities. Aim 2 will determine whether Cer regulates IFN-β signaling and antiviral defense, and whether the subcellular location of Cer influences its role as a pro- or anti-viral signal. Together, these studies will determine how IFN shapes and is shaped by SPLs, providing fundamental insight into the role of these lipids in the earliest steps of antiviral innate immunity.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY With the most people ever in history currently living with HIV, finding a cure remains a global priority. Non-human primates (NHPs) are a clinically relevant model for developing strategies for HIV cure. The safety and efficacy of therapeutic curative approaches in ART-suppressed SIV-infected NHP have provided the basis for several strategies currently in human clinical trials. While the current daily ART regimen has advanced preclinical SIV cure research, it has its drawbacks. In addition to the high costs for staffing and drug administration, daily ART injections require daily manipulation of the NHP and unintended immune activation and perturbation from the carrier molecule Kleptose. Long-acting ART offers a novel and promising therapeutic approach as an alternative to both treat and prevent HIV. However, the impact of LA-ART on the latent viral reservoir is unknown and may alter approaches to cure HIV. Here, we are proposing to use LA-ART therapeutically in SIV-infected rhesus macaques to achieve full viral suppression. In specific aim 1, we will determine the ability of a long-acting antiretroviral regimen to achieve durable viral suppression in SIVmac239-infected rhesus macaques and assess the impact on the latent viral reservoir. In aim 2, we will characterize the safety, tolerability, and pharmacokinetics of repeated dosing of long-acting ART regimen and evaluate its effects on anti-SIV immunity. The results generated here will be directly compared to previously published historical controls that received conventional daily ART. This work will provide a safe and viable alternative to current daily antiretroviral therapies and lay the foundation for the next generation of ART in non-human primates.

NIH Research Projects · FY 2026 · 2026-01

Project Summary The liver is one of the most important organs for gene therapy of both inherited and acquired disorders. In non-fibrotic livers, the hepatocytes are accessible from the systemic blood circulation due to the fenestration of hepatic sinusoids. For this reason, most liver-directed gene therapy today is administered systemically, typically by intravenous injection. However, the systemic route of administration has several disadvantages. First, every organ is exposed to the gene therapy agent, leading to potential off-target effects. Second, the effective concentration of the vector is significantly diluted by the large blood volume. Finally, the normally patent sinusoidal fenestrations are closed in cirrhotic liver disease, limiting access to hepatocytes in fibrotic conditions. However, an alternative route of administration that potentially abrogates these limitations also exists. The liver is accessible via its biliary duct system and the use of this approach remains largely unexplored for gene therapy. In this application, we propose to systematically explore the intraductal route of administration for multiple gene therapy modalities. We have three lead hypotheses: 1) The biodistribution profile of gene therapy vectors will be improved by ductal injection and less off-target effects will be observed; 2) The effective dose of the gene therapy agent will be significantly lower compared to systemic administration and 3) Efficient hepatic transduction can be achieved in liver cirrhosis. We will explore two important liver gene therapy modalities, testing rAAV in Aim 1 and RNA nanoparticles in Aim 2. The utility of the intraductal route will be tested by delivering IGF-1 to cirrhotic rats.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY/ABSTRACT Myelin is vital to neuron health and function, as it provides insulation and metabolic and trophic support to axons. In many neurological diseases, such as multiple sclerosis, myelin is damaged and lost. In such cases, myelin repair is often incomplete, leaving axons chronically demyelinated. This is thought to leave axons susceptible to subsequent degeneration. Thus, finding novel strategies to promote remyelination is of the utmost importance in treating demyelinating diseases. Myelin formation is a metabolically demanding process as oligodendrocyte progenitors (OPCs) differentiate and expand their membranes. During developmental myelination, OPCs signal to promote angiogenesis, helping to build a robust vascular network capable of delivering the metabolites necessary to support OPC differentiation and myelin formation. However, how adult OPCs meet their metabolic demands during active remyelination after white matter injury remains unknown. This application focuses on the role of lactate in the metabolic coupling of OPCs with CNS vasculature in the context of active remyelination. The preliminary data presented here demonstrate that lactate dehydrogenase A (LDHA), the enzyme for converting pyruvate to lactate during glycolysis, in OPCs is necessary for proper angiogenesis and myelination during development. Further, mouse models of demyelination experience vascular remodeling and expansion during remyelination, which is coupled with increased expression of the lactate transporter, MCT1. This proposal will test the hypothesis that during remyelination, OPC-encoded Ldha promotes vascular network expansion through endothelial-MCT1 and lactate uptake, and that the resulting vascular network supports functional axonal remyelination and conduction. This will be done using a wide array of genetic, pharmacological, and proteomic approaches focusing on understanding how OPC-Ldha (Aim1) and endothelial-MCT1 (Aim 2) function to coordinate CNS vascular remodeling and remyelination. In the first aim, I will use the Cre-lox system to delete Ldha specifically in oligodendroglia. Using the cuprizone model of demyelination, I will assess vascular remodeling and functional remyelination in control and Ldha-knockout mice. I will also isolate mitochondria from the oligodendroglia for use in proteomic experiments in order to determine the metabolic role of LDHA in remyelination. In Aim 2, I will use shRNA to knock down Mct1 specifically in endothelial cells. This will be done in the Myrf-knockout model of demyelination. These mice will be assessed for alterations in remyelination and brain vascularization. The completion of the experiments and training plan outlined in this application will provide exceptional training opportunities that will enhance and expand my technical skills and further my knowledge of glial and vascular biology. It will also produce the data necessary for future funding applications that will allow me to carve out a research niche as an independent investigator.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurodegenerative disease that places a significant physical, emo- tional and financial burden on patients, their caregivers, and society at large. Current estimates indicate that >50 million individuals globally are living with AD, and this number is projected to surge to 150 million by 2050. While the exact pathogenesis remains undefined, AD is characterized by aggregation of abnormal extracellular amy- loid-beta (Aβ) plaques and intracellular tau neurofibrillary tangles, which may precede symptom onset by up to a decade. Recent advances in Aβ clearing therapies for AD have shown promising efficacy in slowing cognitive and functional decline. However, these treatments only benefit those in the earlier stages of AD, and curative intervention for late-stage AD does not yet exist. In light of emerging therapies, early diagnosis of AD would substantially improve patient quality of life and reduce the rapidly escalating AD health care costs. However, symptoms of early stages of AD are often mild and difficult to quantify, making accurate early-stage diagnosis a significant challenge. Tremendous efforts have been focused on the development of Aβ-targeted contrast for AD diagnosis. While Aβ-specific positron emission tomography (PET) brain imaging is now FDA approved, it is ex- pensive, requires radiotracers and patient exposure to ionizing radiation, rendering it unsuitable for early diag- nostic screening on a large population. Since the retina is a neurosensory extension of the brain, the strong connection between retina and cerebral pathology makes the retina a promising target for the development of novel imaging tools for early AD diagnosis. It’s been shown that Aβ accumulation in the retina of AD patients can mirror brain pathology, especially in the primary visual cortex. In this proposal, we aim to develop the first fluo- rescence-based, non-invasive imaging technology for the early detection of AD by visualizing and quantifying Aβ content throughout the retina using topically applied, near-infrared (NIR) Aβ-specific fluorophores formulated in eye drops. The proposed contrast agents represent remarkable opportunities for the discovery of a NIR fluor- ophore with superior specificity and sensitivity for Aβ. These fluorophores will undergo extensive validation stud- ies in rodent AD models and in human AD brain and retina tissues. Preclinical pharmacology and toxicology of the eye-drop formulated NIR Aβ-specific fluorophores will be completed. In parallel, the capabilities of a NIR ultrawide field fluorescence scanning laser ophthalmoscope to provide a comprehensive view of Aβ in the retina will be demonstrated. Finally, sensitivity assessment for early AD detection using fluorophore eye drops and retinal fluorescence imaging will be quantified in rodent AD models with varying Aβ burden. Topical ocular ad- ministration of AD-specific fluorescent contrast agents offers significant advantages, including non-invasive ad- ministration with the potential for self-administration, simple application that can increase patient compliance, and low cost that can facilitate mass screening programs. Overall, our approach has the ultimate translational goal of enabling truly non-invasive screening for early AD across large populations through simple eye drops.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY Oligodendrocytes (OLs), glial cells in the central nervous system, critically contribute to neuronal conduction and health. OLs wrap axons in insulating myelin sheaths – increasing conduction speed – and shuttle metabolites to the local axon to provide necessary energetic support. OLs generate throughout life, deriving from a dedicated pool of OL progenitor cells (OPCs) that tile the brain. Oligodendrogenesis, or the differentiation of OLs from OPCs, is modulated in adulthood by neuronal activity; new OLs and myelin form at increased rates on circuits activated by artificial stimulation or learning and memory tasks. This activity-dependent oligodendrogenesis is consequential for circuit function; across a variety of paradigms, the irreversible genetic blockade of oligodendrogenesis prior to learning results in significantly impaired behavioral performance. Furthering our understanding of the roles adult-born OLs play on neuronal circuits will greatly expand our understanding of neural-glial interactions and assist in determining the extent of functional benefits potentially garnered by therapeutics that induce oligodendrogenesis. This study investigates the cellular biology and circuit interactions of adult-born OLs, using a novel knock-in mouse line enabling the selective labeling and delayed ablation of new OLs generated after a designated time. We first propose to use in vivo two-photon imaging through cranial windows to track and visualize the generation, loss, and replacement dynamics of OLs and myelin in this model, determining the timeline of events occurring after ablation is induced and whether OLs demonstrate cellular age- related resistance to ablation. Data acquired in this aim will provide interesting insight into the cellular and subcellular changes adult-born OLs undergo in response to ablation. To elucidate the functional contribution of activity-generated OLs on neuronal circuitry, we will use a contextual fear conditioning paradigm to induce oligodendrogenesis. Rather than blocking the generation of new OLs after learning, a common model in the field, we will permit OLs to generate and integrate onto neuronal circuitry before ablation and use post-ablation freezing behavior to determine whether the sustained integration of OLs is required for fear memory. The data and knowledge gathered from successful completion of these aims will provide valuable insight into the cellular and circuit dynamics of adult-born OLs.

NIH Research Projects · FY 2025 · 2025-12

Project Summary Connexin 46 and 50 (Cx46/50) gap junctions are critical for maintaining lens transparency, and disruption of proper gap junction function results in the world’s leading cause of blindness: cataract. Cx46/50 gap junctions couple adjacent lens fiber cells together and regulate the lens microcirculatory system, which is responsible for circulating ions, nutrients, and waste products from the oldest to the newest cells. Lens fiber cells rely on anaerobic mechanisms to generate ATP; thus, over time the intracellular pH drops below physiologically neutral conditions. In vitro experiments have shown that Cx46/50 gap junctions are gated under low pH conditions – providing a plausible mechanism contributing to age-related cataract. Preliminary structural data demonstrates that annular membrane lipids can intercalate the inner pore of Cx46/50 under conditions at pH 5.8, and that this pore lipid gating phenomenon is reversible when proteins are returned to pH 7.4. However, it is completely unknown how lipids enter and exit the pore and even if lipids functionally gate Cx46/50 gap junctions in a cellular context. Therefore, the primary goals of this project are to 1) determine the functional role of lipids on Cx46/50 pH gating in a cellular environment and 2) determine the mechanistic pathway of lipid entry into the pore of Cx46/50 gap junctions. For Aim 1, my approach will employ a combination of a chemical biology toolkit together with cellular functional assays to determine the role of lipids in the pH gating of Cx46/50 in a cellular environment. Additionally, suspected pH-sensing amino acid residues will be systematically mutated to determine their role in pH-induced channel closure. For Aim 2, my approach will use a combination of structural biology methods utilizing cryo-electron microscopy together with proteomic approaches to detail the protein-lipid interactions that define the pH-dependent translocation pathway of lipids into the Cx46/50 pore. Success in these studies will clarify critical mechanistic details of how Cx46/50 functionally interact with lipid membranes to respond to intracellular changes in pH. These insights are expected to provide molecular level insights into age-related cataract, with potential broad relevance to understanding how other connexins respond to pH-induced stress conditions.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY Social disconnection in humans, particularly during adolescence, is associated with substance use disorder vulnerability. In mice, adolescent social isolation profoundly alters reward processing in adulthood; increasing the preference for drugs of abuse, enhancing associative learning, altering dopaminergic signaling and transcription within the BLA and extended reward circuitry. Intriguingly, these phenomena are all also associated with thyroid hormone signaling. Further, dysregulation of thyroid hormone in early life is associated lifetime risk for reward-related mood disorders and altered development of monoaminergic systems. In adults, thyroid hormone dysregulation is associated with substance- and alcohol use disorders. Therefore, we propose that the persistent impacts of adolescent social isolation result from transient dysregulation of thyroid hormone signaling during the sensitive period of adolescence. Thyroid hormones, when bound to their receptors, are transcription factors that mediate various epigenetic processes and regulate gene expression. Aberrant thyroid hormone signaling at critical developmental periods persistently alters transcription in other tissues through epigenetic reprogramming of thyroid hormone sensitive genes. Despite its critical role in neurodevelopment and its link to substance use disorder, the consequences of thyroid hormone dysregulation in adolescence, a key period for reward circuitry development and substance use disorder vulnerability, is virtually unknown. Our preliminary data suggest that circulating thyroid hormones and expression of its receptors are transiently disrupted in adolescence by social isolation and this is associated with enhanced expression of GABAergic neuronal markers in the adult basolateral amygdala (BLA), a key reward-related brain region Here, we will test the hypothesis that thyroid hormone is critical for development of the basolateral amygdala (BLA) during adolescence and that isolation-induced disruptions to the thyroid hormone system result in lasting epigenetic reprogramming of the reward circuitry to increase cocaine sensitivity. First, we will determine how adolescent social isolation impacts thyroid hormone-mediated transcription in the BLA (Aim 1). Then we will determine if thyroid hormone dysregulation induced by adolescent isolation disrupts cell-type specific transcriptional profiles within the BLA (Aim 2). Finally, we will disrupt thyroid hormone receptor beta levels specifically during adolescence to determine its role in reward-related behavior in (Aim 3). Together, these foundational studies will establish a role for thyroid hormone-mediated programming of the BLA and uncover novel mechanisms of isolation-induced reprogramming of SUD vulnerability during adolescence - an endpoint that has become even more urgent given the known reductions in social interactions due to the mitigation of Covid-19 for the current generation of adolescents.

NIH Research Projects · FY 2025 · 2025-09

Project Abstract Autistic children experience some of the lowest health care quality and highest unmet needs of any pediatric chronic condition. Additionally, disparities persist in service use and life course outcomes among autistic people. These problems exist because (1) we have not adequately assessed which outcomes are most essential for autistic children and their caregivers, and (2) few large-scale studies have assessed which individual and family factors, service use factors, and local/state environmental features are associated with optimal and suboptimal health outcomes. The proposed project, Advancing Success and Developmental Outcomes in Autism Spectrum Disorder through the Analysis of Secondary Data (ASD3 Outcomes), will fill these evidence gaps by linking multiple large, population-based data sets providing rich information on various factors driving health outcomes for autistic children. By the end of this project, we will have generated actionable evidence to guide national and state-level strategies for improving health outcomes for autistic children ages 1–17 years. Leveraging cutting-edge data science methodologies including multi-source data harmonization and deep learning, this initiative will identify the most salient predictors of optimal and suboptimal outcomes among children and youth, examine geographic and demographic disparities in these outcomes, inform system-level interventions, and advance evidence-based policy change to improve health for autistic individuals. First, we will assemble a community advisory panel of autistic youth and adults, parents and caregivers, and health and educational providers, and a technical advisory panel of autism and data science researchers. We will use the panelists’ expertise to identify key health and educational outcomes that can be measured in Medicaid claims data in all 50 states, the National Survey of Children’s Health (NSCH) in all 50 states, and/or Early Intervention state data (HI, IN, MN, OR, VT). Next, we will use the NSCH to create state-level, age-specific Autism Quality Indices that measure factors driving health outcomes for autistic children at different developmental stages. We will apply these indices, along with child-level demographic markers, neighborhood measures (using the Child Opportunity Index 3.0), and other state health and education systems variables, to model key outcomes in Medicaid Claims and State Early Intervention data, through interpretable machine and deep learning models. Finally, we will translate evidence into action by harnessing the collective expertise of our community and technical advisory panels to develop recommendations based on the community-engaged and data- driven findings generated. These efforts will produce actionable insights to guide policy, programs, and practice that optimize health outcomes for autistic children and their families nationwide. We will disseminate this work broadly.