Stanford University

NIH Research Projects · FY 2026 · 2023-01

Skin disease is constantly changing over time; rashes flare, moles grow, ulcers heal, and chronic skin disease severity fluctuates over time. Patients only see dermatologists at infrequent and irregular intervals that do not match the clinical course of the disease. As clinicians and researchers do not have an easy way of monitoring skin disease in between formal clinical visits, valuable granular information about skin disease progression, flares, and improvement in response to treatment, is currently being lost. The number of people in the United States older than 65 years is growing. By 2030, 20% of all Americans will be older than 65 years, making the geriatric population the same size as the pediatric population. The incidence of dermatologic conditions is rising in parallel, with more than 27 million visits to dermatologists each year. Yet transport difficulties, limited mobility and increased fall risks make frequent clinic visits challenging for frail older adults. The COVID-19 pandemic has accelerated the adoption of teledermatology; however, our qualitative interviews with dermatologists, older adults and caregivers highlight substantial barriers with current mobile health tools, with no readily accessible way to monitor skin disease at home. There is an urgent need for a user-friendly tool for older patients to collect photographs, symptoms and monitor their skin disease from home. We propose to expand our novel, older adult-friendly, teledermatology virtual assistant – Dermatology for OldeR Adults (DORA) – to support clinical disease monitoring. DORA facilitates skin disease monitoring from home, instead of in-person clinic visits. Our preliminary data show that DORA is easier for older adults to use compared to current teledermatology platforms because it enables image collection using simple conversational text message reminders, without requiring high technology literacy. In this study we will: 1) Develop a longitudinal image library of common skin conditions affecting older adults including all skin types using DORA. We will oversample participants with skin of color to address healthcare disparities arising from under-representation of skin of color in dermatology images. 2) Describe the progression and natural history of common skin diseases affecting older adults by observing patterns and patient experiences of older patients who use DORA. We will compare the information collected virtually through DORA to in person clinical assessments at 6 and 12 months. 3) Conduct semi-structured interviews with physicians from diverse healthcare settings to identify barriers and solutions to implementation and clinical utility of home-based digital monitoring of skin disease. Successful completion of these aims will result in a novel, readily accessible way to monitor skin disease in older adults from home, reducing burdensome or unnecessary clinic visits while maintaining quality of life. This approach can be used in other settings where technology literacy barriers and unequal access to dermatologists contribute to healthcare disparities.

NIH Research Projects · FY 2026 · 2022-12

Project Summary The past two decades of cancer research have identified one or more drivers for most human malignancies. In addition, multiple cell death genes and pathways have been identified that normally protect the organism against developmental mutations or defects in genomic maintenance. These observations suggest that one might be able to rewire the transcriptional circuitry to cause the cancer cell to kill itself with its own driver. We have invented a new class of molecules that use Chemically Induced Proximity (CIP) to rewire the cancer cell such that the cancer driver activates proapoptotic pathways. We call these molecules Transcriptional Chemical Inducers of Proximity or TCIPs because they induce proximity or recruit a cancer driver to the promoters of proapopotic genes. For development of these two-sided, “bifunctional” molecules, we will focus on Diffuse Large Cell B Cell Lymphoma (DLBCL), using the master inhibitor of cell death, BCL6, as an anchoring transcription factor on the promoters of proapoptotic genes. For an activator we use any of several aberrantly-expressed transcription or epigenetic activators, to simultaneously derepress and activate proapoptotic genes. We have synthesized bifunctional small molecules that recruit transcriptional activators over-expressed in DLBCL to the promoters of proapoptotic genes normally bound and repressed by BCL6. In our preliminary studies, these molecules lead to rapid and robust killing of DLBCL that is superior to the best-in-class inhibitors and also specific for cells that over-express the targets of the bifunctional molecule. Using a strategy similar to genetic dominant gain-of-function mutations, TCIP can engage cancers with multiple drivers, thereby going beyond conventional inhibitors and degraders. Because bifunctional molecules rely on two separately overexpressed proteins, TCIP takes advantage of the natural, fundamental basis of transcriptional specificity to provide precise, predictable and selective killing of cancer cells. To further develop this approach, we will first optimize these molecules for stability, solubility and specificity of killing of DLBCL. Secondly, we will define the mechanism by which they produce robust and rapid killing. Finally, we will test them in established PDX models. Our studies will involve a multidisciplinary approach drawing on expertise in chemistry, clinical lymphoma treatment, cancer biology and genomic biology. If successful, we will lay the foundation for a new concept in the treatment of lymphoma, and more broadly, cancer chemotherapy, that is more specific than many existing approaches. The use of a novel dominant gain-of-function strategy by TCIPs addresses the issue of treatment of cancers, such as DLBCL, that have multiple, concurrent drivers.

NIH Research Projects · FY 2026 · 2022-12

Innate Allorecognition in Clinical Organ Transplantation Slow attrition of organ allografts after the first post-transplant year (long-term graft loss) remains a significant problem in clinical transplantation. We hypothesize in this grant application that innate allorecognition – the activation of recipient monocytes by allodeterminants on graft cells – is an important driver of long-term graft loss in kidney transplant recipients. Innate allorecognition stimulates monocyte differentiation into antigen-presenting, cytotoxic, and innate memory cells that propagate the adaptive alloimmune response or cause graft damage directly. A key allodeterminant responsible for innate allorecognition and memory is the polymorphic transmembrane molecule Signal Regulatory Protein Alpha (SIRPa). Based on compelling mouse and human data, we propose to test in Aim 1 the clinical hypothesis that SIRPa mismatch between the donor and recipient is a significant, independent risk factor for chronic alloimmune injury and long-term graft loss. Two large cohorts of donor/recipient kidney transplant pairs on whom granular clinical and protocol biopsy data are available will be genotyped and studied. In Aim 2, we will test the mechanistic hypothesis that the adverse effects of SIRPa mismatching are mediated via recipient monocyte activation and differentiation. Phenotypic, transcriptional, and functional analysis will be performed on peripheral blood monocytes, coupled with spatial profiling of biopsy samples. We believe that the proposal is significant because the SIRPa genotyping strategy can be readily translated to clinical practice, and mechanistic insights gained can lead to druggable targets. The proposal is innovative because it explores a novel concept, innate allorecognition, that goes beyond the traditional T, B, and Ab-centric approaches to the rejection problem and one that has not been explored in humans yet.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY / ABSTRACT Although its molecular mechanisms remain to be clarified, the anatomic basis of cognitive impairment in Alzheimer's disease (AD) is injury and degeneration of synapses. Subpopulations of neurons in different brain areas may be more or less susceptible to specific types such insults Yet, molecular characterization of synapses in AD and AD–related dementias (ADRD) is limited, leaving the factors underlying this selectivity and the fidelity of widely-used mouse models to the human condition unclear. Here, we propose to fill these important gaps in selective cell vulnerability in aging and AD by identifying molecular signatures to suggest or confirm cellular pathways that may mediate vulnerability. The proposed project will accomplish this using a unique tissue resource and novel technology developed by us, and couple them with cutting-edge machine learning (ML) techniques to enhance differential signals and achieve deeper insights into the factors underlying selective neuron vulnerability or resilience. The novel technology that we have developed is called Synaptometry by Time-of-Flight, or SynTOF, and it provides an unparalleled opportunity for multiplex molecular analysis of millions of single synaptic events. We will build on our preliminary data, which coupled this new technology with ML approaches to gain novel insights into synaptic injury in AD, including in a transgenic mouse model that regionally overexpresses amyloid (A) β peptides in neurons, and which highlight the value of SynTOF in discovering the molecular patterns of injury in human synaptic subtypes, as well as assessing the fidelity of mouse models at the single synaptic level. Drawing on our unique tissue resource of cryopreserved synaptic preparations from participants with extensive clinical, genetic, and neuropathologic annotation, novel and powerful technology, and robust computational approaches, we propose to test the hypothesis that synapse injury in AD and ADRD is disease-, brain region-, and synapse subtype-specific, thereby highlighting new targets for therapeutic intervention and determining the extent to which three commonly used transgenic mouse lines model the synaptic injury of humans. When successfully completed, our novel resources and approach will provide unique insights into pre- and postsynapse subtype-specific mechanisms of injury at unprecedented scale, and further highlight new therapeutic targets for AD and ADRD.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY Alzheimer’s disease (AD) is a neurodegenerative disease that is the most common cause of dementia. AD encompasses a range of pathophysiologic processes including accumulation of amyloid-beta, neurofibrillary tau tangles, neuronal degeneration, and neuroinflammation. There is now strong evidence suggesting that changes in brain dynamics during sleep are related to development of underlying neuropathology. Previous studies have examined correlations between scalp EEG features and coarse summary measures of PET amyloid and tau, but the more precise link between neural electrophysiology and amyloid/tau pathology at site-, region-, and network-levels has not yet been analyzed in detail. Characterizing these spatially and functionally specific patterns is critical for future early detection of AD using sleep-related biomarkers, development of sleep interventions to slow disease progression, and electrophysiological monitoring of amyloid/tau-centric treatments. Meanwhile, over the past several years, our group has made significant advances in EEG source localization methods that enable localization of cerebral currents in cortical and subcortical regions at a resolution that is comparable to PET and fMRI. In this project, we propose to measure high-density EEG during sleep in humans, alongside PET and MRI, across the stages of AD from Preclinical to Mild Cognitive Impairment to mild AD dementia.

NIH Research Projects · FY 2025 · 2022-12

Project Abstract/Summary Aging is associated with decline in spatial navigation and episodic memory function. Theoretical models argue that navigation and episodic memory are intricately linked – spatial contexts serve as scaffolds for episodic memory, facilitating the encoding, organization, and retrieval of memories. One set of processes that could contribute to both navigational and episodic memory impairments in aging is diminished attention; reduced attentional control and diminished sustained attention in older adults could lead to poor spatial representation, suboptimal navigational strategies, and subsequent declines in memory. The proposed research program will leverage a series of virtual-reality (VR) spatial navigation paradigms, in combination with behavioral and neural markers of attention, spatial coding, and memory to examine how attentional deficits in aging relate to navigation and episodic memory difficulties. Aim 1 will use a VR spatial navigation task to examine how moment-to-moment selective attention and sustained attention (assessed through eye-tracking and pupillometry) relate to spatial navigation performance in older relative to young adults. Expt 1 will assess both age-related and individual differences in (a) how attention relates to navigation performance, (b) the relative salience of types of spatial cues (distal vs. proximal) that influence navigation strategies, and (c) how attention during initial environment encoding affects the ability to calculate new spatial trajectories following changes in the environment. Aim 2 will investigate how age-related differences in behavioral and neural markers of attention relate to differences in the representation of spatial context and in context-mediated regulation of memory integration and interference. Expt 2 will examine how (a) behavioral measures of attention to spatial context relate to episodic memory, influencing when two overlapping events are discriminated (pattern separation), diminishing interference, and when two overlapping events are integrated, enabling novel inferences. Expt 3 will use fMRI to examine (a) age-related differences in the function of neural systems of attention (e.g., frontoparietal cortical networks, locus coeruleus) and episodic memory (e.g., medial temporal lobe) during spatial navigation and associative encoding, along with concurrent pupillometry to (b) measure how trial-by-trial differences in behavioral markers of sustained attention influence neural representations of spatial context and episodic memory and (c) investigate how age-related differences in interactions between attentional and memory systems influence memory integration and interference. Collectively, these studies will advance and link theories of attention, spatial navigation, and memory to early cognitive, behavioral, and neural changes in aging, and promise to enable future study of how attention, navigation, and memory interactions are affected by disease processes (e.g., Alzheimer’s disease).

NIH Research Projects · FY 2026 · 2022-12

Project Summary How do neurons coordinate alternative energy sources to meet the demands of neural computation? PI:Clandinin The brain is energetically expensive, a metabolic cost that is intrinsic to neural activity and hence a defining feature of how the brain computes. As a result of this energy intensive operation, the main methods for measuring changes in neural activity in humans, such as functional magnetic resonance imaging (fMRI), actually infer neural activity by measuring changes in blood flow, a proxy for local energy consumption. Moreover, many diseases that alter the efficiency and balance of energy production are characterized by profound deficits in brain function. However, how neural activity shapes energy production at the level of individual cells, circuits and across the brain are only incompletely understood, particularly in the context of active sensation and behavior. Longstanding work in the field, based in vitro models of single cells and human neuroimaging, have revealed how different pathways for energy production react to changes in neural activity, responding when increases in neural activity cause depletion of ATP, a core cellular energy currency. Our recent work using the intact brain of the behaving fruit fly build on these results, and revealed a new element to the coupling between metabolism and energy production, namely that cells use current levels of neural activity to predict future energy needs. Thus, this project seeks to answer how the reactive and predictive elements of neural-metabolic energy coupling interact. The proposed work focuses on three key questions. First, do different neuron types, with distinct patterns of activity in the intact brain, display differences in how they react to, and predict, metabolic load? Second, how do neurons balance energy production via two alternative energy sources, namely glycolysis and oxidative phosphorylation, to both react to metabolic cost and predict future expenditures? Finally, how are these metabolic loads coordinated across circuits in behaving animals detecting sensory stimuli? We hypothesize that because neuronal activity levels differ substantially across cell types, and because glycolysis and oxidative phosphorylation can produce ATP with different latencies and efficiencies, subcellular compartments, neurons and circuits dynamically switch between alternative energy sources to both react to computational demand and predict future metabolic need. To test this hypothesis, we propose to use two photon imaging of fluorescent sensors of neural activity and metabolic flux, combined with genetic and optogenetic perturbations of specific cell types, using the adult fruit fly brain as a model. As many of the genes involved in energy metabolism are evolutionarily conserved between humans and flies, deepening our understanding of how neural activity couples to energy metabolism in vivo will increasing our understanding of the neural impacts of metabolic diseases, possibly opening new therapeutic avenues for future investigation.

NIH Research Projects · FY 2026 · 2022-12

Abstract Chronic pain is a pervasive global health issue affecting about 20% of individuals worldwide, but available treatments for chronic pain are still inadequate. Opiates have been used for centuries as potent analgesics, but issues with tolerance, abuse, and overdose have contributed to current opioid crisis in the US. On the other hand, it is well documented that the level of perceived pain can be strongly influenced by cognitive and mood states, revealing the existence of powerful endogenous top-down modulation of pain. However, the therapeutic potential of targeting descending pain modulation pathway in treating chronic pain has not been extensively explored, in a large part because of our poor understanding of the circuitry and molecular mechanisms underlying how these descending pathways engage in chronic pain. In our preliminary studies, we developed novel genetic and viral tools, and gained robust access to the -opioid receptor expressing spinal cord projecting neurons in the rostroventral medulla (OPRM+ RVMSC neurons). We demonstrated that the OPRM+ RVMSC neurons has limited contribution to normal nociception but is required for both initiation and maintenance of nerve injury induced chronic mechanical pain. We therefore established these neurons as a potent cellular target for treating chronic pain. In this proposal, we will further examine the circuitry (Aim1) and molecular (Aim2) mechanisms that engage the OPRM+ RVMSC neurons in chronic pain. These proposed studies will not only advance our understanding of how the OPRM+ RVMSC neurons is recruited in chronic pain, but also inspire the development of novel non-opioid treatment for chronic pain.

NIH Research Projects · FY 2025 · 2022-12

PROJECT SUMMARY Much work has been done to characterize the structural underpinnings of neuromodulatory systems and how these architectural features shape neuromodulator action. Yet, although, neuromodulators primarily signal through volume transmission which requires them to traverse the extracellular space (ECS) from release site to target receptor, neuromodulatory diffusion through the ECS has received little attention. We know from computational models that ECS diffusion is dependent on factors such as volume fraction, tissue tortuosity and ECS geometry. Simulations so far have mainly focused on synaptic diffusion and synaptic spillover mechanisms whereas neuromodulation functions at much larger spatiotemporal scales than that: even neuromodulator diffusion through just layer IV in macaque cortex, for example, requires molecules to travel distances up to 0.5 mm from release site to target receptor. Factors related to tissue porosity become increasingly more important at such distances but current computer models like the common simulation engine MCell are only equipped to study molecular diffusion at the nanometer scale. Consequently, we need updated computational models capable of simulating the diffusion of neuromodulators across greater spatial and temporal ranges capable of incorporating measures that become relevant at that macroscale. For this, I propose to develop a hybrid model which will achieve this critical functionality by combining existing MCell capabilities with large-scale algorithms from models of bulk diffusion. Because ECS diffusion is thought to vary with brain regions which to date has not been systematically evaluated, I will then, with this multiscale model, simulate diffusion of acetylcholine, noradrenaline, and dopamine across different regions of macaque cortex to test how factors such as tissue granularity or tissue anisotropy affect common diffusion metrics (e.g., concentrations, diffusion rates, effective diffusion coefficients, and diffusion tensor). Since neuromodulatory networks have been linked to virtually every brain function, understanding the dynamics of neuromodulator diffusion across the brain is an important step in understanding normal brain function. Furthermore, because changes in ECS dynamics and in neuromodulatory systems have been observed throughout development and normal aging or with neuropathology like stroke-related ischemia and dementia, identifying key parameters that determine signaling outcomes, but also the active processes by which they can be modified, may be key for the advancement in diagnostics and therapeutics.

NIH Research Projects · FY 2026 · 2022-12

Abstract The ability to promote regeneration of the central nervous system remains elusive. Stroke is a leading cause of death and disability and creates immense burdens on stroke survivors, their caregivers, and society. Although acute stroke care has rapidly progressed over the past decades, only a small proportion of the patients qualify for these treatments. This leaves a majority of stroke patients without effective medical therapy to augment their stroke recovery. Biomaterials offer a unique avenue to interact with the nervous system. Stem cell treatments are another emerging stroke therapy that shows promise in both basic and clinical trials. However, the optimal method and environment for stem cell delivery remains unknown. We have developed a new stem cell delivery system (ElectricStem) that utilizes conductive polymer scaffolds to transplant neural stem cells into the stroked- brain. Because the polymers are conductive, electrical stimulation can be combined with the transplanted neural stem cells. We have demonstrated that electrical modulation of transplanted neural stem cells dramatically improves stroke recovery over traditional stem cell transplantation alone. In our preliminary studies, electrical modulation of neural stem cell transplants also increases the production of endogenous stem cells in the brain – suggesting a possible mechanism for this improved recovery. Further investigation about the role these endogenous stem cells play in stroke recovery will identify important stroke recovery mechanisms. By evaluating what proteins are upregulated in the transplanted neural stem cells that receive electrical modulation, we have identified stanniocalcin-2 (STC2) as an important pathway for improved recovery. STC2 is a glycoprotein with paracrine effects that plays a role in cell turnover and survival. If STC2 production is increased in transplanted neural stem cells, the animals have improved functional outcomes, and we see greater numbers of endogenous stem cells produced. If STC2 levels are decreased in the stem cells, the improvement in function and endogenous stem cell production is lost. Our proposed research investigates the ability of ElectricStem to recruit endogenous stem cells and alter their activity within the injured rodent brain tissue following stroke. The effects of electrical modulation on the transplanted neural stem cells and host brain will be evaluated in relation to the STC2 pathway. The project will also evaluate if STC2 is a potential therapy for stroke recovery. Finally, our ElectricStem system will be used in a translational aged rodent model to determine if the promising functional improvements seen in young adult animals are observed in older animals. Using these new techniques, we aim to test the hypothesis that augmentation of important endogenous recovery pathways via bioengineered systems will improve neural repair following stroke.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY Adoptive cell therapy (ACT) using engineered T cells – such as chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells – is an effective immunotherapy for hematologic malignancies. Success with ACT has been elusive for solid tumors, which present unique challenges to T cells. ACT also requires conditioning chemotherapy to deplete a patient’s endogenous T cells, which results in significant toxicity. Our goal is to engineer T cells with synthetic functions to overcome hurdles of ACT for solid tumors including the need for conditioning chemotherapy, which would dramatically improve the feasibility and safety of this therapy. In this proposal we use the orthogonal IL2 cytokine-receptor pair developed by our collaborator Dr. Garcia at Stanford. Orthogonal IL2Rβ (o2R) is only activated by the orthogonal IL2 (oIL2) cytokine, and not by wildtype IL2. When activated, o2R signals through the intracellular domain (ICD) of IL2Rβ, which involves cooperation with the native common gamma chain (γc). Leveraging this cooperation, we studied chimeric orthogonal receptors in which the IL2Rβ ICD of o2R is replaced with ICDs of receptors for other γc cytokines, such that oIL2 elicits the corresponding γc signal. Of these chimeras, signaling through the IL9R ICD (o9R) generated a unique STAT phosphorylation profile and differentiation trajectory, prompting further exploration in vivo. Despite a weaker proliferative signal than o2R signaling, o9R signaling resulted in T cells with superior anti-tumor efficacy, an effect pronounced in the absence of lymphodepletion. To translate this finding into a viable treatment for patients with advanced solid tumors will require an understanding of the functional features of o9R signaling T cells that permit their anti-tumor efficacy, especially in the absence of conditioning chemotherapy. Our preliminary data led us to focus on two of these features, which we tackle in Aims 1 and 2. In Aim 1, we focus on the peripheral in vivo effects of o9R signaling that rely on interaction with the host, especially lymph node homing and priming. We hypothesize that the o9R signaling reprograms T cells in the periphery for efficient lymph node homing and spatial positioning that promotes priming that is critical for their anti-tumor effects in vivo. Aim 1 will use both TCR- and CAR- based syngeneic mouse solid tumor models of ACT. In Aim 2, we turn to the cell-intrinsic effects of o9R signaling on effector capacity in the face of chronic antigen stimulation. We hypothesize that o9R signaling interferes with the epigenetic changes that drive T cell dysfunction in the context of chronic antigen stimulation, resulting in superior effector capacity. Aim 2 will primarily use human T cells engineered with a TCR specific for the NY-ESO-1 antigen along with the pmel model. Our complementary aims outline an approach to define the effects of IL9R signaling in T cells that underlie their anti-tumor functions in solid tumors without conditioning chemotherapy. Our findings will set the stage for the therapeutic translation of T cells endowed with IL9R signaling.

NIH Research Projects · FY 2025 · 2022-09

Health care algorithms make decisions that impact the lives of millions of individuals, yet few are rigorously evaluated for impact after they are implemented. Unfortunately, these oversights have led to the perpetuation negative health impacts. In an effort to leap ahead of the current state of the field, our research would build a framework for assessing the impact of health care algorithms before they are deployed, which is a novel line of investigation. This proposal is inherently interdisciplinary, spanning machine learning, AI, health economics, decision sciences, statistics, health policy, and qualitative research. Mathematical decision science microsimulation models will be developed, positing an underlying complex causal network of the health care system. In order to initialize these microsimulation models, a broad collection of data sources will be used, including health care billing claims, primary care electronic health records, and qualitative information. Primary outcomes under consideration center health care access, quality, and costs. Robustness and rigor are central to our work. Despite no comparator framework existing, we will additionally develop simpler causal network models along with Markov cohort models to provide a basis for comparison. Outputs produced will also be freely shared in the form of open-source code and open-access preprints featuring transparent descriptions of all models and assumptions. This work would involve a substantial shift in focus for the Principal Investigator; pivoting to research that leverages mathematical decision science modeling and qualitative approaches while merging them with her expertise in machine learning for health care. Importantly, this framework has the potential to influence a new set of standards and guidelines for AI algorithms, establishing a blueprint where tools are routinely evaluated for impact before deployment. Thus, creating this first-of-its-kind impact framework could transform the development and application of algorithms in health care, representing a substantial paradigm shift with broad impact.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT The molecular mechanisms responsible for the initiation of diabetic retinopathy (DR), and the primary cellular targets of diabetes in the retina have not been fully elucidated. This represents a significant barrier to the development of effective therapies to prevent or slow down the initiation of the disease. When challenged by diabetes, retinal neurons, glia, and the vasculature all display abnormalities. Even though it is currently not clear which cell types are the primary targets of diabetes, Müller glial cells (MG), as one of the first responders of diabetes in the retina, are essential for the development of diabetic retinopathy. However, the molecular mechanisms controlling the diabetes-induced Müller glial responses remain understudied. We applied single cell transcriptomic analysis (single cell RNA-seq) to systematically profile diabetes- induced multicellular responses in the retina of diabetic rat models (preliminary studies). Among the 53 types of retinal cell detected by single cell RNA-seq, MG were one of the first responders to diabetes at the transcriptional level. Notably, MG initially upregulated genes that play protective roles in other systems, including anti-apoptosis, anti-proliferation, anti-oxidation, and anti-inflammation genes, but failed to maintain expression levels of these protective genes as the disease progressed. This failure could contribute to the development of DR. We hypothesize that MG exert protective roles by upregulating protective genes in the early stage of DR, and that enhancing this intrinsic protective mechanism will protect the retina from diabetes- induced damage. The proposed studies will test this hypothesis in two aims. In Aim 1, we will focus on studying one of the candidate protective genes, Zinc finger protein 36 homolog (Zfp36), which was initially upregulated by diabetes in MG and then downregulated as DR progressed, using diabetic rat models. In Aim 2, we will determine whether multiplexing activation of protective pathways in MG with a novel CRISPR-based technique can further protect the retina from diabetes-induced damage. In summary, the proposed study aims to uncover the roles of MG in initiating DR, focusing on dissecting their protective effects. This work will lead to better understanding of DR and new therapeutic candidates.

NIH Research Projects · FY 2026 · 2022-09

PROJECT SUMMARY Multiple sclerosis (MS) is a devastating neuro-degenerative disease that causes visual impairment in young, middle aged and older adults with resulting substantial lost productivity and cost to society. Current thinking attributes vision loss in MS to death and dysfunction of the retinal ganglion cells (RGCs) that comprise the optic nerve. However, there is only weak correlation between visual function and RGC atrophy, and some patients without RGC atrophy have vision loss, suggesting that all relevant contributors to vision loss in MS have not been identified. We have discovered structural features in the foveal avascular zone (FAZ) of retinas of the majority people with MS and fewer people with glaucoma that cast a shadow on the photoreceptor layer and correlate with visual function. Our discovery contributes to addressing gaps in understanding visual pathway involvement in MS, offering new windows into diagnosis and treatment of vision loss in MS. This project studies the recently discovered FAZ features in retinas of people with MS and related diseases using adaptive optics scanning light ophthalmoscopy, a high resolution, non-invasive, state-of-the-art imaging technique. In the first aim, the relationship between central visual function and FAZ features will be defined using MS as an experimental model. Advanced microperimetry will be used to test the hypothesis that photoreceptor shadowing is the mechanism of vision loss. In the second aim the cause and composition of the FAZ features will be inferred through longitudinal studies of people with MS, cross sectional comparison between MS, glaucoma and related neurological and ophthalmic diseases and histopathological study of ex-vivo MS eyes. In the third aim rapid imaging protocols will be developed to enable faster detection of FAZ features and these will be applied to estimate the distributions of FAZ features in the populations with MS, glaucoma, other diseases and controls. These observations will evaluate the candidacy of the FAZ features as biomarkers of MS by defining specificity. The immediate impact of this research will be advancing understanding of vision loss in MS, developing rapid imaging strategies to enable broader study of large sample sizes at multiple sites and evaluating FAZ features as biomarkers in MS, glaucoma and other disease.

NIH Research Projects · FY 2025 · 2022-09

In response to the National Institutes of Health RFA-DA-22-050, we herein propose a HEAL Data2Action Research Adoption Support Center (RASC). The main purpose of the RASC is to stem the tide of overdose death in the US by leading a scientifically-driven support endeavor designed to effectively translate evidence-based interventions for substance use disorders and pain. Implementation science (IS) is the methodological bridge to both the scientific and public health gaps. Yet implementation science is understudied and underutilized in response to the opioid epidemic. Emblematic of heightened awareness for implementation scientific potential, the HEAL D2A Program will be launched. The program features 10-12 Innovation Projects, and, in addition to the RASC, two additional centers: Modeling and Economic Resource Center and Data Infrastructure Support Center. The RASC will optimize and elevate the IS capability of the overall HD2A program. In this OVERALL component, we document how the RASC is organized into four synergistic and dynamic cores: Administrative, Substance Use Implementation Support Core, Pain Implementation Support Core, and a Research & Evaluation Core. Three overarching specific aims are strategically ordered across the RASC and all its cores as follows: To ASSESS the current state of the HD2A Innovation/Acceleration Projects on implementation research capability, and develop an empirically-based catalog of evidence-based and emerging interventions for substance use disorders and pain; to ASSIST on how Innovation/Acceleration Projects can improve implementation methods and measures through on demand technical assistance and the use of an innovative Implementation Support Plan, and to develop SUD and Pain Intervention Implementation Resource Guides; and lastly, to ADVANCE the HD2A Innovation Projects toward greater potential for scalability and sustainment. The RASC is led by 4 MPIs with demonstrated track records of implementation research in the fields of substance use and pain interventions: McGovern (Stanford), S. Becker (Northwestern), W. Becker (Yale) and Brown (Northwestern). The MPIs are joined by complementary expert core co-directors and have assembled an unmatched roster of highly-qualified leaders in these fields—carefully selected, organized and ready to provide the necessary implementation support across the HD2A program. This RASC meets all the specified requirements as outlined in the RFA. What distinguishes this RASC is our bold ambition to enhance not only the implementation capability of the HEAL HD2A program, but to influence the field far beyond the confines of the HD2A initiative. We intend to elevate implementation science in substance use and pain intervention research and thereby ensure ubiquitous access to proven interventions by the people and communities who need them the most.

NIH Research Projects · FY 2024 · 2022-09

Project Summary In the U.S., approximately 400,000 newborns require resuscitation every year. The decisions made and interventions performed in those first minutes of life can determine whether the child lives, dies or survives with significant lifelong morbidity. Neonatal resuscitation is a time-pressured activity requiring teams to coordinate invasive procedures in a specific sequence of steps. Because error rates in excess of 50% during neonatal resuscitation have been reported, enhancing the effectiveness and safety of those interventions will have a profound impact on the number of lives saved, the quality of life for survivors, and the annual cost of neonatal intensive care (which currently surpasses $25B). This work will focus on improving three specific aspects of neonatal resuscitation: the design of the physical workspace, decision making during this invasive procedure, and human-technology interaction. We will assess the range of neonatal resuscitation environments currently in use and, via simulation and iterative design, explore different room configurations to determine the layouts that facilitate enhanced team performance. We will investigate how to display key anatomic and physiologic data, detect data that is trending negatively, and alert staff before an actual threat becomes manifest. We will also experiment with methods of minimizing patient handling and reducing the need for manual adjustments of devices that produce imprecise results and interfere with patient care procedures. To accomplish these aims this proposal brings together experts in clinical neonatology, resuscitation, engineering, human factors, human-centered design and healthcare simulation. This project is significant in several ways. First, by taking a systems engineering approach to neonatal resuscitation, examining how individual subsystems (patients, healthcare professionals, physical environments, equipment, supplies, interventions, data, regulations, culture) impact the overall system, we will develop a comprehensive model that identifies multiple potential points of intervention for improving patient care. Second, because even the most uncomplicated delivery occurring in a low-acuity, low-volume hospital or birth center can evolve within minutes to become a life-threatening emergency for the newborn, the benefits of this work will be generalizable to every facility where pregnant women give birth – rural, inner city, urban and suburban. Third, this study focuses on neonates, including those born to Black, Latino, Indigenous and Native American, Asian American, Pacific Islander and LGBTQ+ women, all of whom represent AHRQ priority populations. Finally, the results of this work will extend well beyond the neonatal population, as they will be applicable to improving human and system performance in other complex, safety-critical, time-pressured healthcare domains involving the surgical, emergency and intensive care of pediatric, obstetric and adult patients.

NIH Research Projects · FY 2024 · 2022-09

Abstract There is a critical need for RNA sensors in living mammalian cells. With the advent of single-cell RNA sequencing, the transcriptome of any cell type is readily obtainable if not already available. In contrast, we are still in urgent need for a universal method to act on such transcriptomic information. If we can genetically express arbitrary effector proteins in specific cell types according to their transcriptional markers, we would transform large swaths of basic research and biomedical applications, such as immunology, neuroscience, and cancer therapy. In addition, we would like such sensors to be programmable and operate at the post-transcription level. One promising use case that would benefit from such sensors is cancer ablation, using an approach dubbed “circuits as medicine”, where a genetic vector encoding an entire “circuit” (metaphor for a collection of biomolecules engineered to regulate each other and implement specific functions) is delivered intracellularly. The circuit will sense the cellular states based on hallmarks of cancer (i.e., the overexpression of specific RNAs or the presence of specific mutations), process the signals, and deliver specific therapeutic payloads accordingly in cancer cells, directly killing them while educating the immune system to search and destroy other cancer cells. Previous efforts largely relied on strand displacement, a successful strategy for nucleic acid-based signal processing outside cells. However, their functionality has remained inadequate inside living mammalian cells, most likely because the double-stranded RNA (dsRNA) formed during strand displacement signals viral infection and are actively engaged by mammalian proteins in the immune pathways. We hypothesize that, because it is impossible to evade the omnipresent dsRNA-interacting proteins, it is wiser to embrace them. In this proposal, we will leverage endogenous human enzymes that recognize and specifically edit dsRNA, to create sensors that can be programmed to respond to arbitrary RNA transcripts (“triggers”). First, we will use fast design-build-test cycles in vitro to optimize sensor performance. We will focus on increasing sensor output in response to triggers by engineering the sensor configuration and its sequence choice, and we will characterize how the sensor affects and is affected by the cellular context. Second, to enable the quantitative distinction of different trigger levels and the integration of multiple triggers, we will engineer threshold-setting modifications and AND logic gates. Third, leveraging the unique post-transcriptional nature of such sensors and gates, we will combine them with mRNA or an oncolytic RNA virus as delivery vectors, which has traditionally been difficult to control. Last by not least, we will validate the performance and the therapeutic potential of the sensors, gates, and the RNA vectors in cancer cell lines. The future directions of the proposed project include continual optimization of the sensors, logic gates, and vectors, testing them in more realistic cancer models including mouse models and patient-derived organoids, and applying the tools to other fields.

NIH Research Projects · FY 2025 · 2022-09

Gradual loss of brain function and neurodegeneration are common features of aging throughout diverse phyla. Senile dementias, including Alzheimer’s Disease (AD), likely involve failures of adult neural stem cell (NSC) number, viability, and/or functions. Our lab studies NSC’s role in central nervous system (CNS) development, adult regeneration, and in onset dementia such as AD. We are establishing a field of research in regenerative medicine and aging as the first lab to prospectively isolate human NSC and use them in published preclinical and clinical trial studies. In this proposal we seek to understand basic principles and evolutionarily conserved elements of NSC involvement in neuronal regeneration, degeneration, and aging in the colonial tunicate Botryllus schlosseri.  Botryllus has two reproductive modes: sexual reproduction which produces a primitive chordate with a simple CNS (the chordate brain), that will undergo metamorphosis into an asexually reproducing sessile invertebrate which propagates by budding. We have found that Botryllus buds contain self-renewing germline stem cells, and somatic stem cells which self-organize to form a colony composed of genetically identical individuals. This stage exhibits weekly assayable CNS tissue regeneration from candidate NSC and undergoes repeated neurodegeneration throughout its adult life, a process that resembles adult neurogenesis and neurodegeneration in vertebrates. Thus, Botryllus offers a unique opportunity to study the cellular and molecular mechanisms of CNS generation and degeneration through observing weekly regeneration cycles in young and old colonies (e.g. <3 months vs. >7 years). We aim to identify the mutations and/or epigenetic changes that accumulate in the NSC, and through self-renewal remain present throughout an organism's life. We have undertaken a systematic molecular (brain transcriptomic) analysis of CNS cells of old and young Botryllus colonies, paired with morphological and behavioral characterization of each of their CNS lineage cells. This analysis revealed 93 homologous genes that correlate with Alzheimer’s disease, including APP, GRN, PSEN1, GLUD2, and VPS35 that are differentially expressed between young and old colonies. Furthermore, the brains of old colonies contain a lower number of cells and have reduced neuron-mediated responses to sensory stimuli. Since stem cells are the only cells that self-renew and are maintained throughout the colony’s life, we hypothesize that genetic mutations or epigenetic changes that accumulate over time in NSC and their progenitors are the main cause of age-related neurodegenerative diseases. To test this hypothesis, we plan to characterize the molecular and cellular diversity of the Botryllus brain in chordate larvae and young and old colonies, isolate their NSCs at the single cell level, identify mutations that accumulate in NSC DNA, and test their effect on brain regeneration and function. Morpholino anti-sense RNAs will also be used to manipulate the activity of genes whose genetic variation predicts the onset of Alzheimer’s disease and test their effect on brain regeneration and degeneration capacity, and also attempt to introduce permanent alterations of their genomes by CRISPR.

NIH Research Projects · FY 2025 · 2022-09

ABSTRACT Substance use disorder (SUD) affects over 20 million Americans, causing personal strife and cost. A major SUD risk factor is hazardous use (HU) of substances during high school (HUSH), when the brain continues to develop, rendering it especially sensitive to environmental factors. Identifying the effects of and risk for HUSH generally focuses on selected interactions between fixed (i.e., trauma, demographics) and modifiable (i.e., mental health, emotion, environment, behavior, sleep) factors, and occasionally brain development features differentiating substance using and non-using cohorts. Results have yielded limited improvements to risk assessment. Thus, we propose a paradigm shift in the study of HUSH, replacing measurement selection and population splitting with mapping individuals to comprehensive multi-dimensional measures. The objective of our novel data-driven process is to identify constellations of fixed and modifiable factors forecasting HUSH in individuals. As our analysis is based on public data sets that include brain imaging, we will document interactions of those constellations with neural circuits to determine neuromechanistic underpinnings of HUSH. Myriad factors influence hazardous substance use, such as the fixed contributors of sex and family history of SUD; the modifiable factors of unhealthy sleep habits, peer pressure, and risk-taking propensity; and brain development characterized by an atypical imbalance between emotion and control network. We will model this heterogeneity via machine (deep) learning technology identifying constellations of measurements in line with our hypotheses regarding prevention, i.e., modifiable behaviors interacting with anomalies in neuroadaptation forecasting HUSH initiation. Aim 1 will forecast initiation of HUSH in the last years of high school based on the closest visit before turning age 16 years for no/low substance users in National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA, N =350) and confirm findings on the larger Adolescent Brain Cognitive Developmental cohort (ABCD, N>11K). HUSH will be defined by substance use criteria recorded through annual self-reports and refined by weekly surveys administered via cell phones. Aim 2 will create a self-supervised learning model explicitly tracking over time interactions across modifiable behaviors, fixed factors, and brain circuits important for hypothesis testing. We will cross-validate the model by identifying HUSH for each high school year and forecast based on data collected prior to high school. We will explore dynamically updating the model as data are acquired to predict resilience, i.e., youth who abstain from hazardous substance use during high school, despite having risk factors such as traumatic and untoward COVID pandemic experiences. Each aim is linked to hypothesis testing concerning factors that can be altered to mitigate the risk of HUSH. This project will be the first to provide patterns accurately forecasting the risk of HUSH on an individual level. Accurately computing this risk would be foundational for enhancing prevention efforts.

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY Precision engineering of the gut microbiota requires a mechanistic understanding of how microbes interact with host physiological pathways in order to produce desired health outcomes. In stunted children, commensal gut microbes have been correlated with aberrant host inflammation and growth impairment, but mechanisms underlying these associations are poorly understood. Mouse models have suggested causality, but they fail to recapitulate the dynamics of the mucosal immune system in humans and the complexity of the human gut microbiota. This project will interrogate these questions in vivo in a cohort of >1500 children from rural Bangladesh at risk for stunting, for which biological specimens were collected longitudinally from 0-3 years of age. Preliminary analysis of 16S rRNA gene sequences from >3700 fecal samples collected from these children has identified a Bifidobacterium sequence variant that is highly correlated with intestinal inflammation and subsequent growth faltering. In Aim 1, I will identify strain-specific microbial genes that might mediate these observed associations. In Aim 2, I will interrogate the mechanistic underpinnings by evaluating microbial small- molecule metabolites in feces and blood associated with high levels of Bifidobacterium and concurrent gut and/or systemic inflammation in children 14 months old. In Aim 3, I will use advanced latent variable statistical modeling to determine the importance of associated groups of microbial (taxonomic, metagenomic, and metabolic) and host (gut and systemic inflammation) features on future growth faltering. I will also estimate the maximum achievable improvement in child growth from a theoretical, 100% efficacious microbiota-manipulation intervention, providing an expected effect size for comparison with other intervention alternatives. This work will increase our mechanistic understanding of the associations between early life gut microbiota and aberrant intestinal/systemic inflammation as well as future growth faltering, producing new options for predictably manipulating the gut microbiota to mitigate adverse health outcomes. The proposed project will provide a rigorous training experience in the fields of gut microbiota, microbial metabolites, multivariate statistics, and pediatric gastroenterology under the mentorship of a group of scientific experts, and will equip me with the skills necessary to become an independent researcher.

NIH Research Projects · FY 2026 · 2022-09

The rise of fentanyl and stimulant use have dramatically worsened the national public health crisis of substance use in the US. The substance use epidemic continues to threaten hard-fought gains in prevention and control of HIV and hepatitis C virus (HCV) and related diseases. Identifying the best approach to reduce HIV and HCV transmission stemming from the substance use epidemic is of critical public health importance. In this extension to our MERIT award, our overall aims remain the same, but we seek to extend our work to encompass the intersecting syndemics of opioid use, stimulant use, and other related conditions. We will: 1. Model the effect of the opioid and stimulant epidemic on transmission of HIV, HCV, and related diseases. 2. Model the epidemiologic and population impacts of individual strategies to prevent and mitigate the harms of opioid and stimulant use on HIV, HCV, and other disease-related outcomes. 3. Model the epidemiologic and population impact of portfolios of strategies to mitigate the harms of opioid and stimulant use on HIV, HCV, and other disease-related outcomes. 4. Model the impact of barriers (e.g., lack of access to substance use services) and enablers to implementation of effective strategies and portfolios of strategies to reduce the harms of opioid and stimulant use. Our work will provide clinicians, policymakers, and community organizations with critically needed guidance about strategies to mitigate the consequences of opioid and stimulant use and improve length and quality of life and for people with substance use disorder.

NIH Research Projects · FY 2025 · 2022-09

Summary Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating disease of unknown etiology that affects millions, with an estimated 2.7-6.3% of women, who are disproportionately affected, meeting the diagnostic criteria. IC/BPS is characterized by persistent pelvic pain, pressure, or discomfort arising from the urinary tract and is accompanied by increased urgency and frequency of urination. These symptoms are highly disruptive to everyday life, and current treatments fail to address the underlying causes of IC/BPS, which remain enigmatic. Pain management is an essential aspect of treatment, and incorporates opioid-based analgesia in 28% of patients within a month of diagnosis, presenting significant risks of addiction. Whereas its pathogenesis remains unclear, IC/BPS is commonly associated with bladder sensory hyperinnervation, which aligns with the clinical picture of increased sensitivity to pressure or noxious stimuli. Effective treatment, however, must also address dysfunction of the protective bladder epithelium (urothelium), as indicated by the association of flare-ups (up to 1/3) with urinary tract infections that injure the urothelium and by the near total loss of the urothelial barrier in severe IC/BPS with Hunner’s lesions (10-20% of patients). Our mouse data, including scRNA-Seq (single cell RNA sequencing), pinpoint a specialized compartment of bladder mesenchyme that functions in the regulation of both bladder sensory innervation and urothelial integrity. This specialized mesenchyme, termed SAM (sensory nerve-associated mesenchyme), appears to integrate signaling inputs from the general circulation, from neighboring bladder cell types including urothelium, and from nociceptive neuronal termini to generate a mesenchymal instruction set that underlies sexual dimorphism in bladder nociception and maintenance of urothelial integrity. Our preliminary data also present a molecular compendium based on scRNA-Seq of samples from normal human and IC/BPS patient bladders. This IC/BPS cell atlas suggests that SAM dysfunction in signal processing and integration may constitute a central common feature underlying and unifying the diverse manifestations of IC/BPS, and we propose to confirm and extend these preliminary findings by expanding our cell atlas to include samples from multiple disease stages. Further investigation based on these findings may identify SAM-specific signaling pathways as novel therapeutic targets for IC/BPS intervention. Aim 1 of our proposal will focus on local and systemic signals that elicit SAM production of neurotrophins, whereas Aim 2 presents preliminary studies showing that sensory neurons innervatint the bladder can profoundly affect the urothelium, likely acting through neuropeptide signaling to SAM. Modulating these signaling pathways with non-toxic pharmacologic agents in animal models of IC/BPS, as outlined in Aim 3, will provide the basis for effective new treatments, which may obviate the need for opioid use in pain management, thereby eliminating the risk of addiction.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Eliciting or suppressing an adaptive immune response has become central to oncology, autoimmunity, and infectious disease. Checkpoint inhibitors have revolutionized the treatment of cancer, while TNF inhibitors and other immune-suppressive biologics have become the standard of care in autoimmune diseases. Vaccines are a stunning accomplishment of biomedical research; the mRNA vaccines for SARS-2 are only the latest example. CAR-T cells induce long-term remission in acute lymphoblastic leukemia, a previously incurable disease. However, current methods for modulating adaptive immunity have serious limitations. Checkpoint inhibitors and biologics only work in a subset of patients, and global stimulation or suppression of immune function frequently leads to autoimmunity or opportunistic infection. Despite their extraordinary properties, many vaccines require a needle and a cold chain, making them difficult to deploy in low- and middle-income countries, and they fail to induce mucosal immunity, so vaccinated people can infect others. Engineered T cells have not been successful against solid tumors to date, and ex vivo T cell engineering is costly and difficult to scale. Here, we propose to address these challenges by tapping into the host’s ‘colonist interaction program’. Certain bacterial strains from the microbiome elicit a strikingly potent, specific, and durable immune response. In a new unpublished project in the lab that inspired the work we propose here, we showed that the anti-commensal immune response can be redirected against the host by engineering commensal bacteria to express host antigens on their surface. Commensal bacteria have all the key attributes of an ideal vaccine vector: they induce highly potent, antigen-specific T and B cell responses; colonization is durable on the timescale of years to decades (experimental evidence suggests the same is true for the immune response they elicit); and colonists modulate immune function safely, in a way that spares host tissue from autoimmune attack. Our vision is to create a general platform for eliciting a potent and durable adaptive immune response in a way that is safe and inexpensive. The kernel of our idea is to develop a set of vaccine scaffolds in which a commensal is the adjuvant and colonization is the mode of administration. We propose a four-part process to build the foundations of commensal vaccines: Goal 1: identify a core set of commensals with immune modulatory properties; Goal 2: optimize CD8+ T cell induction for antitumor therapy; Goal 3: enhance B cell induction for preventing viral infection; and Goal 4: redirect colonist-specific Tregs against autoimmune disease. These goals can proceed in parallel, and success in any one of them would have a great deal of impact. We note that although this work is applied, it will create useful tools for basic research into immune modulation by the microbiome, just as biologics and methods for T cell engineering have done for other sub-disciplines of immunology.

NIH Research Projects · FY 2025 · 2022-09

Overall, the small bowel and colon are organs critical for maintaining homeostasis of the human body by mediating nutritional absorption upon the ingestion of food. Though both organs are extensive in length, there are known differences in function and cellular heterogeneity within different portions of each. Also, a cross section anywhere in the bowel reveals a complex layering of components involved in absorption and secretion, motility of gut contents, circulation, and immunity. In this submission, we propose to continue our efforts in the Stanford Tissue Mapping Center (TMC) to produce multi-modal, three-dimensional single-cell resolution maps of the small bowel and colonic wall structure. This will serve as a community resource to further study intestinal function and disease. We will collect tissues from deceased organ donors with explicit consent for distribution among the HuBMAP consortium and broad access genome data sharing (GDS). Three sets of technologies will then be employed. Tissue samples will be subjected to single-nuclei ATAC-seq and RNA-seq. These open chromatin and transcriptomic profiles will be spatially mapped to tissue sections using the CODEX (CO-Detection by indEXing) multiplexed spatial immunoassay. We will also employ the Molecular Cartography multiplexed fluorescence in situ hybridization (FISH) assay to enable more accurate integration of CODEX and single-nuclei data. The resultant three- dimensional maps will span all layers of the bowel wall and include the epithelial, enteroendocrine, vascular, lymphatic, nervous, immune, and muscular cell populations that contribute to normal bowel function.

NIH Research Projects · FY 2025 · 2022-09

There are fewer individuals entering into the fields of classical hematology and pediatrics as well as positions of leadership. In addition, it is critical that more hematology researchers are trained to better understand the field and study diseases that are relevant to hematology in order to improve outcomes. We have developed an innovative, multidisciplinary training program in classical hematology with faculty mentors who have unique expertise and experience training students and fellows. The goal of this training program is to recruit local community college and undergraduate students to Stanford University to 1) obtain an introduction to clinical aspects of classical hematology; 2) participate in didactic lectures and laboratory experience in hematology research, 3) be exposed to ethics in research; and 4) explore career options in hematology. Given the declining number of translational and basic researchers interested in hematology research, a training program in hematology will be critical to fill the pipeline and ultimately increase the number of leaders in the field of hematology. In this application, we seek funding for 10 community college or undergraduate students each year to spend 8-weeks during the summer with a member of the training program faculty with expertise in hematology research. Students will have the opportunity to perform research in one of the 15 expert faculty mentors’ laboratories. Trainees will be selected from a pool of >200 eligible high school graduates from cities throughout the country and >1400 students from 26 local community colleges surrounding Stanford University. The funding will support the students’ salaries and supplies for the mentor. The students will participate in an 8-week didactic course consisting of lectures, workshops, and research seminars. Lectures will focus on introduction to classical hematology and various research techniques. Career development workshops for trainees include writing scientific abstracts, giving presentations, ethics, and preparing posters. Students will also receive “hands on” experience with appropriately matched mentors and their trainees, e.g. postdoctoral fellows, based on the students’ interests. There will be a poster symposium at the end of the program. The Program Directors and Internal Advisory Committee will evaluate the program annually. The External Advisory Committee will review the R25 program every year and meet with the Program Directors, Internal Advisory Committee members, and students. The R25 program will be evaluated by the student participants every year. We will utilize the strengths of Stanford University to recruit promising students to hematology research to train future leaders in the field.