Indiana University Indianapolis

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY The maintenance of skeletal muscle mass is not only required for activities of daily living, but it is critical for the prevention of metabolic diseases such as type 2 diabetes. Resistance training and the mechanical loading of skeletal muscle are known to stimulate muscle hypertrophy and glucose metabolism; yet the molecular basis underlying the ability of mechanical loading to stimulate these processes is still not well understood. The long- term goal of this research is to develop novel therapies that mimic the beneficial effects of mechanical loading on muscle size and glucometabolic health. Our overall hypothesis is that mechanical loading stimulates muscle glucose uptake via a currently unknown glucose transport mechanism to not only fuel the energetic and biosynthetic demands of muscle hypertrophy, but also to direct the transcriptional response to loading. The rationale for this work is based on studies in which genetic deletion of the two main glucose transporters found in skeletal muscle did not impair mechanical load-stimulated muscle glucose uptake. It is also based on studies in which mechanical loading stimulated glucometabolic flux and preserved hypertrophic growth in high fat diet- induced insulin resistant skeletal muscles. To test the overall hypothesis, the following specific aims were proposed: 1) Identify the glucose transporter(s) activated by mechanical loading in skeletal muscle; 2) Determine if glucose uptake is necessary for mechanical load-stimulated muscle hypertrophy; and 3) Determine if enhanced muscle glucometabolic flux is necessary for the transcriptional response to mechanical loading. The first aim will involve incubating mechanical load-stimulated muscles in a glucose photoaffinity reagent to capture active cell surface-localized GLUTs and then determining their identity using mass spectrometry-based analyses. The second and third aims will involve administering mice with a new small molecule GLUT inhibitor to block mechanical load-stimulated glucose uptake in vivo. The second aim will focus on examining the inhibitor effects on muscle size and protein synthesis, whereas the third aim will focus on examining the inhibitor effects on the metabolic and transcriptional responses to loading. The proposed research is innovative because it focuses on the use of unbiased molecular, biochemical, and physiological approaches to not only identify the GLUT(s) responsible for mechanical load-stimulated muscle glucose uptake, but to provide novel mechanistic insight into the relationship between glucometabolic flux and the transcriptional alterations needed for muscle hypertrophy. The proposed research is significant because it will identify novel genes and proteins that are part of the molecular mechanism by which mechanical loading stimulates myofiber hypertrophy and glucometabolic flux. This is a key first step towards the generation of therapies aimed at increasing muscle size and improving muscle metabolic health for the treatment of individuals with chronic muscle wasting or glucometabolic diseases.

NIH Research Projects · FY 2026 · 2026-06

Project Summary & Abstract: The major serine/threonine phosphatase, protein phosphatase 1 (PP1), is involved in many different biological processes throughout the body. Phosphatases like PP1 are known to “keep things in check” to limit adaptive changes from occurring under pathological conditions. Unlike their kinase brethren, serine/threonine phosphatases are more substrate promiscuous. This has historically led to the notion that they are “undruggable.” However, phosphatases like PP1 associate with myriad targeting and inhibitory proteins that permit appropriate regulation of spatial and temporal signaling. Specifically, PP1 associates with over 200 proteins that target and/or inhibit its activity at specific sets of substrates. However, knowledge of how specific proteins regulate PP1 targeting and function are poorly described. Spinophilin and neurabin, collectively termed the neurabins, are the two most abundant brain postsynaptic density (PSD)-enriched PP1 targeting proteins. While the neurabins are PSD and brain enriched, they are also located throughout the body. Moreover, we and others have found that the neurabins play roles in myriad different disease-induced adaptations, including neurological disorders, cancers, immune function, and obesity and diabetes. However, due to a lack of genetic tools, our understanding of how the neurabins impact pathological adaptive changes associated with disease is unclear, In this “Focused Technology Research and Development” R01 proposal, we will leverage our current cell type-specific spinophilin and neurabin knockout mice, as well as develop novel tools to identify and compare the spinophilin- and neurabin-specific interactomes across cell types. We have generated constructs that allow for Cre-dependent epitope tagging of spinophilin and neurabin with an ALFA epitope tag as well as an UltraID proximity ligase that we show leads to robust, specific, and selective pulldown of spinophilin and neurabin protein interaction networks in overexpression studies. To permit in vivo studies, we will generate transgenic animals to allow for tissue and cell type-specific isolation of endogenous spinophilin and neurabin interactors. These studies will validate that these approaches allow us to delineate unique and overlapping spinophilin- and neurabin- specific interacting proteins within specific cell types, setting the stage for future studies to determine how disruption of specific or overlapping interactions impacts pathological adaptations associated with a range of disorders. Successful completion of these studies will enhance our knowledge and ability to “drug” selective PP1 holoenzymes.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY / ABSTRACT Colonoscopy reduces the risk of colorectal cancer (CRC) mortality through the detection and removal of pre- cancerous polyps (adenomas), but the magnitude of risk reduction depends upon the quality of the colonoscopy. Most colonoscopy quality improvement (QI) initiatives have focused on higher-volume gastroenterologists. In rural and peri-urban communities in the United States, most colonoscopies are performed by lower-volume colonoscopists, who are mostly surgeons, and CRC outcomes are worse compared to urban areas. These lower- volume colonoscopists have marked variability in quality and many fail to adhere to best practices or meet national benchmarks. Higher adenoma detection rate (ADR) is the quality metric most associated with reduced CRC mortality. However, ADR is less accurate at lower colonoscopy volumes, suggesting that ADR alone cannot reliably differentiate quality or provide meaningful information to improve quality in lower-volume colonoscopists. Thus, alternative methods to measure and improve quality in lower-volume colonoscopists are needed. Video evaluation of procedures such as colonoscopy is a valuable tool for assessing and improving technical skills in multiple specialties. In prior work, we found that higher-volume gastroenterologists’ colonoscopy skill, assessed by expert evaluation of video-recorded colonoscopies using a validated technical skill scoring rubric, is highly correlated with quality metrics requires fewer colonoscopies for accurate assessment, and correlates with ADR. Further, we showed that delivery of focused feedback based on technical skill scores improves colonoscopy quality. While expert video evaluation of colonoscopies is an effective tool to measure and improve quality in lower-volume colonoscopists, it is not feasible on a larger scale given the time and cost of manual video review. We therefore developed and validated an AI-based tool that identifies key steps in colonoscopy videos, for rapid expert review and scoring. This study focuses on the implementation and evaluation of an AI-augmented intervention to improve colonoscopy quality of lower-volume colonoscopists in rural and peri-urban areas to ultimately reduce CRC mortality. The intervention, the “Colonoscopy Quality Improvement Bundle” (ColonQI Bundle), combines (1) AI-augmented expert assessment and scoring of technical skills; (2) AI-augmented automated calculation of quality metrics (e.g., ADR, withdrawal time), and (3) Targeted feedback of specific technical skill deficits based on the scores (audit-feedback, structured video-based didactics, coaching, mentoring). Lower-volume colonoscopists, with a focus on surgeons will be recruited to: (1) Assess the needs and preferences of, and select strategies for implementation of the ColonQI Bundle using an implementation science framework; (2) Implement the ColonQI Bundle, using tailored implementation strategies tailored to the needs and preferences of lower-volume colonoscopists; and (3) Assess the effectiveness of the ColonQI Bundle to improve colonoscopy quality and technical skills among lower-volume colonoscopists.

NIH Research Projects · FY 2026 · 2026-05

Project Abstract White matter hyperintensities (WMHs) are common findings in older adults, appearing as high-signal areas on T2-weighted MRI scans. While often linked to cerebral small vessel disease, they reflect non-specific changes in white matter composition and have been linked to a wide range of conditions, including neurodegenerative diseases. This non-specificity makes it difficult to determine the underlying cause of WMHs based solely on their size or location on an MRI scan. The challenge becomes even more pronounced in dementia clinics, where distinguishing between the different causes of WMHs is crucial but complicated by the interplay of Alzheimer’s disease (AD) and aging, vascular cognitive impairment and dementia (VCID). These conditions often coexist, contributing to white matter damage, making it harder to isolate their individual contributions. Without a clear understanding of WMH pathologies, the relationship between AD and VCID will remain unsolved, and tailored interventions will remain challenging. To address this gap, we propose an innovative multimodal-neuroimaging approach that integrates modern advanced techniques. The proposed project aims to identify distinct imaging features that characterize the mechanistic, cellular, and hemodynamic aspects of diffuse white matter disease in AD vs. VCID. By employing advanced neuroimaging techniques, including diffusion MRI for cellular microstructure, perfusion MRI for blood flow, and quantitative susceptibility mapping for microbleed and myelination, we will develop an individualized analysis approach to characterize WMHs. This comprehensive approach will differentiate the pathophysiology of periventricular versus deep-brain WMH in relation to AD and vascular risk factors. The goal is to distinguish WMH related to AD from those linked to cardiovascular issues, ultimately improving diagnoses and enabling more personalized and effective intervention for patients facing cognitive decline.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Chronic diseases affect ~60% of the US population and many of these diseases have been linked to changes to the modern diet. Among these changes has been an increase in the consumption of ultraprocessed food containing very high salt contents. Salt is critical to human health since it provides a source of sodium required to maintain tissue homeostasis and support various physiological functions. However, excess salt consumption can be detrimental to human health. In addition to causing hypertension, excessive salt consumption can have an impact on immune function. Recent studies have demonstrated an impact of high salt diets on certain innate immune functions, on CD4 T cell differentiation and function and may temporarily enhance the CD8 T cell response to certain tumors. However, little is known about the impact of excessive salt consumption on CD8 T cell responses to viral infections. Our new preliminary data demonstrate that mice fed a high salt diet have reduced CD8 T cell function during an acute viral infection leading to a delay in viral clearance and an increase in virus-induced morbidity. In addition, virus-specific CD8 T cells from mice fed a high salt diet adopt a functional and phenotypic profile reminiscent of T cell exhaustion that normally occurs only during chronic viral infection. Thus, our data support that excessive salt consumption impairs CD8 T cell responses to viral infection and favors the development of T cell exhaustion. In this proposal, we will test the central hypothesis that excessive salt consumption rapidly impairs the capacity of CD8 T cells to respond to viral infections through both extrinsic and intrinsic mechanisms. We will address this hypothesis with 2 specific aims. In specific aim 1, we will determine the extrinsic T cell mechanisms through which excessive salt consumption impairs CD8 T cell responses to viral infection. In specific aim 2, we will identify the intrinsic T cell mechanisms by which excessive salt consumption impairs CD8 T cell responses to acute viral infections. Our work will reveal the fundamental biology underlying the regulation of CD8 T cell function by a key nutrient that is overconsumed by a large proportion of the human population. In addition, our research will provide new therapeutic targets and/or dietary interventions aimed at restoring CD8 T cell function in patients who consume excess dietary salt and experience viral infections. Thus, this work has the potential to significantly improve human health outcomes.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT The candidate’s long-term goal is to develop a research program focused on how intergenerational trauma contributes to alcohol use in youth, and thereby facilitate the development of improved strategies to prevent alcohol use disorder (AUD) in youth. Through the research and training in this K08 proposal, the PI will acquire training in longitudinal research methods, AUD clinical and neural correlates, and task-evoked functional MRI (fMRI) connectivity. Youth alcohol use is a serious public health problem that is related to family functioning. Maternal history of post-traumatic stress disorder (PTSD) may increase youths’ likelihood of alcohol use and later risk for AUD by influencing youth neurobiology. Heightened response to negative emotions is an important predictor of later AUD in youth and is also associated with family history of PTSD. Associations between maternal history of PTSD, youths’ neurodevelopment, and prospective youth alcohol use have been minimally examined. Addressing this gap in knowledge would support the ability to successfully prevent or mitigate the emergence of AUD in offspring of mothers with a history of PTSD. Therefore, the proposed K08 project will address the candidate’s training goals while gathering preliminary and feasibility data supporting the next step in her research. The proposed research study aims to: (1) evaluate differences in alcohol use among youth with or without a maternal history of PTSD, during a 2-year follow-up period; and (2) among these same two groups, evaluate differences in task- based functional connectivity among brain regions involved in emotion response and corresponding behavior. The PI proposes to accomplish these aims by collecting fMRI and report-based data from a sample of 56 youth ages 12-14, and their mothers with histories of trauma exposure. Half of the youth will have a mother with a history of PTSD, and the other half will not have a mother with a history of PTSD. Youth will complete a fMRI paradigm designed to elicit activity in brain regions underlying emotion response. Youth will complete follow-up assessments every 6 months across 2 years. It is anticipated that findings will show the extent to which maternal PTSD is associated with youth alcohol use, and with disruptions in youth emotion response system function as a potential mechanism. This K08 application proposes training and research that is directly in line with NIAAA objectives and represents a logical progression from the PI’s prior experience to address career development goals in three areas: (1) longitudinal participant retention and analytic techniques in alcohol use research; (2) assessment of clinical and neural correlates of AUD; and (3) advanced functional MRI connectivity methods in developmental models of AUD. The experience and findings from the proposed K08 will position the PI to pursue NIH funding and build this line of research through a large developmental study of AUD risk.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT This project is a Mentored Clinical Scientist Research Career Development Award (K08) application for Dr. Jamie Felton, an Assistant Professor of Pediatrics at the Indiana University School of Medicine. Dr. Felton completed clinical training in Pediatric Endocrinology and has both clinical and research interests in the development, diagnosis, and management of type 1 diabetes (T1D). Dr. Felton’s specific interest is understanding the genetic and metabolic mechanisms that govern B cell tolerance so that key molecular pathways can be targeted for intervention and prevention. Her long-term goal is to become an influential and independent translational clinician scientist who is well equipped to make significant contributions to the field of diabetes and autoimmunity. Dr. Felton’s commitment to a career in T1D translational research lies squarely within the mission of the NIDDK to not only uncover the fundamental cellular and molecular pathways that drive T1D development, but also to foster exceptional training and mentoring of early investigators to ensure continued research progress. HLA variants confer the highest genetic risk for islet autoantibody seroconversion and T1D development. However, up to 30% of individuals with high-risk HLA develop transient islet autoantibodies, implicating an autoimmune response that has been successfully regulated secondary to non- HLA genetic variants. Cellular metabolic pathways in B cells have been shown play important roles in controlling autoimmunity and maintaining tolerance checkpoints throughout B cell development. The goal of this proposal is to investigate how non-HLA genetic risk variants influence B cell metabolism to drive the loss of B cell tolerance in T1D. Dr. Felton will test the hypothesis that genetic variants drive expression of key B cell metabolic and regulatory genes, influencing progression or regulation of T1D in individuals with high genetic risk, with two specific aims. In aim 1, she will define the protective mechanisms of non-MHC alleles in a mouse model of regulation; in aim 2, she will determine the impact of genetic variants on B cell metabolism during human T1D development. Completion of these aims will define how genetic variants shape B cell metabolism to alter T1D outcomes. This K08 award includes a 5-year training plan designed to achieve 4 main goals: 1) expand her repertoire of molecular biology and immunology techniques, 2) gain proficiency in analysis of large omic datasets, 3) develop expertise in approaches to translational research, and 4) cultivate skills necessary to become an independent investigator. Her training plan incorporates strong mentoring, formal technical training, hands-on experience, and didactic coursework. It will be completed within Indiana University’s top 10 NIH- funded Department of Pediatrics, which provides a highly supportive environment for physician scientist development. Completion of the proposed plan will provide training and preliminary data to support an R01 application and propel Dr. Felton toward a career as an independent investigator dedicated to using basic science and translational approaches to solve critical, clinical problems.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY This investigator’s proposal describes a 5-year project of vertebral body derived mesenchymal stem cells within a Thread Reinforced Encapsulation Device (THRED) to treat the acute and long-term effects of mesenteric ischemia. The proposal evaluates intestinal organ recovery after treatment with cellular therapy and evaluates the metabolic and cellular host responses to massive surgical small bowel resection. The proposal provides basic and translational applications of emerging technologies relevant to the surgical treatment of intestinal ischemia. Investigators hypothesize that H2S is a critical component of VB-MSC mediated intestinal protection during mesenteric ischemia treatment, and that encapsulated MSCs can provide a stable source of H2S via an implantable, retrievable delivery system. They have developed a novel mouse with a mutation to test their hypothesis that VB-MSCs release hydrogen sulfide that then reacts at Cysteine440 on eNOS to bring about improved mesenteric blood flow. Through additional models, they investigate how VB-MSCs can be safely delivered within an implantable, retrievable, nanoporous device that allows cells to release their beneficial paracrine mediators while protecting them from host immune deletion. They propose three Specific Aims: 1) Develop a novel cellular delivery system to effectively deploy hydrogen sulfide from VB-MSCs in mesenteric ischemia, 2) Evaluate the interaction of THRED packaged VB-MSCs, H2S, and Nitric Oxide (NO) on chronic mesenteric vasodilation and long-term intestinal adaptation, and 3) Deploy THRED packaged VB-MSCs in a porcine model of mesenteric ischemia as final preclinical testing of scalability and effectiveness. The investigator is a pediatric surgeon scientist who completed his K08 funding through the NIDDK and was previously awarded an Early Stage Investigator R01 through the NIDDK. His career goals are to use this R01 to develop novel therapies and diagnostic tools for intestinal ischemia. He has collaborated with Dr. Minglin Ma at Cornell University who has extensive experience with implantable devices. Dr. Ma’s group has invented the THRED device, which is an electrospun nanoporous membrane that allows stem cells to interact with their local environment, while also containing them in a specific anatomical location and protecting them from immune destruction. Dr. Markel has also collaborated with Dr Tim Lescun, a large animal veterinarian at Purdue University which is approximately 45 minutes away from Dr. Markel’s institution. Additional collaborators include Dr. Erik Woods from Ossium Health, who will supply the VB-MSCs. In summary, this research aims to understand the mechanism that VB-MSCs use to provide acute and chronic protection in mesenteric ischemia. It also looks to identify appropriate delivery strategies so that cells can be delivered in an implantable, retrievable device for therapeutic use. The proposal is highly innovative and the investigator has the appropriate support, collaborations, and infrastructure in place to carry out the study.

NIH Research Projects · FY 2026 · 2026-05

Project Summary The recent rise in adolescent overdose deaths have overwhelmingly involved opioids, particularly illicitly manufactured fentanyl. With illicitly manufactured fentanyl increasingly present in a variety of illicit substances and counterfeit pills and with other substance use (e.g., cannabis, alcohol) predictive of future opioid misuse in adolescents, there is a critical need to target not only opioid use but all substance use among adolescents and to ensure adolescents have access to opioid use disorder (OUD) and other substance use disorder (SUD) services to prevent overdose deaths. Integrating OUD/SUD services into primary care is an approach that may increase the accessibility and availability of adolescent OUD/SUD care. However, when adolescents do receive OUD/SUD services, the quality of these services can vary markedly, with this care not always being timely, developmentally appropriate, or in line with the evidence base. Resultingly, adolescents may drop out of services prematurely or not attain desired outcomes. Thus, a focus on quality alongside access is needed to ensure available OUD/SUD care is safe, timely, effective, and developmentally appropriate. The proposed mentored career development award seeks to improve access to high-quality adolescent OUD/SUD care in primary care through two research aims. In Aim 1, the candidate will define quality indicators for adolescent OUD/SUD care in primary care by conducting a Modified Delphi study with multidisciplinary experts and using existing healthcare quality frameworks. Aim 2 will entail developing a single-session strategies for implementation (S3) approach targeting primary care providers to facilitate implementation of high-quality adolescent OUD/SUD care (Aim2a) and piloting the S3 approach with primary care providers in pediatric primary care clinics to evaluate the S3 for preliminary implementation and effectiveness outcomes (Aim 2b). To conduct this research, the candidate requires training and mentorship in four key areas to address current gaps in training: 1) develop expertise in advanced implementation research (Drs. Aalsma, Adams, Schleider, Wiehe), 2) training in qualitative and mixed methods (Drs. Aalsma, Vest), 3) training in administrative data usage (Drs. Aalsma, Mazurenko, Wiehe), and 4) specialized training in evidence-based OUD and SUD services for adolescents (Dr. Adams). The proposed research and training plan will inform future implementation efforts aimed at improving access to high-quality adolescent OUD/SUD services in primary care and support the candidate’s development as an independent clinical researcher and implementation scientist focused on improving the quality of OUD/SUD care for adolescents in healthcare settings.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Circadian rhythms play a crucial role in maintaining normal physiological functions. However, modern challenges disrupt this finely tuned system, leading to circadian rhythm disruption (CRD) and affecting overall health. Excessive exposure to artificial light, particularly blue light from smart devices, triggers a distinct phenotype of circadian arrhythmia, resulting in sleep deprivation, anxiety, and poor eating habits. Notably, the harmful effects of blue light are especially evident in young adults, impacting circadian photosensitivity and photo perception twice as much as in older adults. In our studies, when healthy adult mice were exposed to a shorter light:dark cycle (10-hour light:10-hour dark, L10:D10) to induce CRD, there were defects in retinal structure and function implicating direct effects of CRD on visual function; however, a biochemical link for the consequences of CRD remains to be elucidated. When we delved deeper to unravel candidate markers, we observed a dramatic decrease in circulating levels of a neuropeptide, orexin. This is particularly relevant because the orexin system promotes wakefulness, thus helping maintain normal circadian rhythms. Based on the above studies, we further performed preliminary studies to demonstrate that orexin mRNA levels in the retina are downregulated coupled with a decrease in melanopsin, a photopigment of intrinsically photosensitivity ganglion cells (ipRGC), together strengthening our premise of studying the consequences of aberrant blue light exposure on visual function and circadian rhythms with potential involvement of orexin related mechanisms. We hypothesize that direct overexpression of orexin will protect against retinal dysfunction and circadian dysrhythmia caused by aberrant blue light exposure. To test this hypothesis, in Aim 1A, we will expose adolescents and adult mice to aberrant blue light conditions in circadian rhythm cabinets. In a group of mice, retinal orexin and melanopsin will be overexpressed. We will perform retinal measurements such as visual acuity, electroretinogram, and SD- OCT. The Aim 1B will characterize the circadian rhythms under the above conditions to assess the effect of retinal orexin and melanopsin overexpression. We will determine the circadian rhythm of wheel-running activity. The outcomes of these studies will help unravel the impact of abnormal exposure to blue light on vision and aid in understanding the consequences of aberrant light exposure on the overall health of adolescents and adults.

NIH Research Projects · FY 2026 · 2026-04

Abstract Indiana University Melvin and Bren Simon Comprehensive Cancer Center (IUSCCC) brings mulƟdisciplinary research teams with experƟse in translaƟonal sciences along with streamlined resources, efficient services, and an insƟtuƟonal environment that fosters innovaƟve clinical and translaƟonal research to the NaƟonal Clinical Trial Network (NCTN). IUSCCC invesƟgators have led trials that defined the standard of care in thymoma, testes, pancreas, and breast cancer. We are commiƩed to leading and supporƟng the next generaƟon of translaƟonal trials within the NCTN. As a Lead Academic ParƟcipaƟng Site we will pursue six specific aims: 1)Integrate genomics, pharmacogenomics, and other molecular assays with tradiƟonal histopathology and imaging to individualize therapy, 2)Lead clinical and translaƟonal research in key rare tumors, 3)Share immunology experƟse across the NCTN, 4)Ensure that all paƟents benefit from the NCTN, 5)Lend experƟse to NCTN operaƟonal efficiency iniƟaƟves, and 6)Mentor junior faculty members to lead the next generaƟon of translaƟonal clinical trials. To accomplish those specific aims, we employ a coordinated clinical trial infrastructure that is efficient and cost-effecƟve, meeƟng the needs of invesƟgators from iniƟal study concept through compleƟon and reporƟng. Overall leadership of the NCTN at IUSCCC is vested in Dr. Kathy Miller, a seasoned invesƟgator who has led three naƟonal trials coordinated by ECOG-ACRIN and recently completed two terms as Co-Chair of the NCI Breast Cancer Steering CommiƩee. Dr. Miller enjoys widespread insƟtuƟonal and mulƟdisciplinary support and is fully empowered to leverage resources to increase accrual and movement of IUSCCC translaƟonal science forward to the NCTN. She is joined in leadership by key invesƟgators in Gynecologic and RadiaƟon Oncology. In this applicaƟon IU will be joined by one affiliate, the Richard A Roudebush VA Medical Center. IUSCCC contributed ~50 paƟents over the most recent 5- year period (3/2019-9/2024) to NCTN; accrual has increased since the pandemic-decline with 79 paƟents enrolled in 2024. Accrual has been evenly split between trials sponsored by ECOG-ACRIN and NRG, together accounƟng for ~80% of our total. In addiƟon, IUSCCC invesƟgators have held key leadership roles within ECOG and the NRG and have made key scienƟfic contribuƟons employing biologic specimens banked as part of cooperaƟve group trials.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Alzheimer’s disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia, with no available cure or disease-modifying therapy. Pathologically, AD is characterized by amyloid beta (Aβ) deposition, neuronal loss, synaptic dysfunction, and glial cell-mediated neuroinflammation. Among inflammatory mediators, SERPINA3, a serine protease inhibitor, has been implicated in AD pathogenesis. SERPINA3 is a major component of amyloid plaques, and its overexpression in glial cells exacerbates AD-like pathology in transgenic mouse models. However, its precise role in disease progression remains poorly understood. To investigate the role of SERPINA3 in AD, we generated a Serpina3-deficient mouse model (Serpina3LD/LD). While the human genome encodes a single SERPINA3 gene, the mouse genome contains a cluster of 14 orthologs. Our model was engineered to delete all 14 Serpina3 genes, enabling a more accurate assessment of SERPINA3 function in disease. Crossing Serpina3 LD/LD mice with the 5XFAD amyloidogenic model resulted in a striking 50 - 60% reduction in plaque burden within the brain of these animals, highlighting SERPINA3 as a key mediator of AD pathogenesis and a promising therapeutic target. While ongoing studies aiming to elucidate the mechanisms underlying this phenotype are under way, here we seek to accelerate translational research by developing and validating a humanized SERPINA3 mouse model in the context of AD. This model will facilitate in vivo testing of SERPINA3-targeted therapeutics, advancing the development of novel treatments for AD.

NIH Research Projects · FY 2026 · 2026-04

Protective immunity to many pathogens involves the production of pathogen-specific high-affinity antibody (Ab). Additionally, allergic immune responses often involve the production of allergen-specific high affinity IgE. A unique subset of T cells, follicular helper T (TFH) cells, are required for helping B cells make high affinity Abs. TFH cells promote and control the germinal center reaction. Germinal centers (GCs) and secondary Ab responses cannot develop in the absence of TFH cells, however excessive development of TFH cells can lead to deregulated Ab responses and autoimmunity. A related subpopulation of follicular T cells, T follicular regulatory (TFR) cells are also important for controlling TFH and germinal center responses. Conventional TFR cells develop from Foxp3+ Treg cells. TFR cells have properties of both regulatory T (Treg) cells and TFH cells. Depending on the specific type of immune response, TFR cells can either inhibit the GC and Ab responses or help promote the GC and the Ab response. How these opposite types of TFR functions are regulated is not well understood. Answering the question of how TFR cells are regulated and how they function has become more complex due to the recent discovery of a subclass of TFH cells that up-regulate Foxp3 and express the same markers used to identify TFR cells. These “Foxp3+ TFH cells” appear to be a new subset of TFR cells. However, the function of Foxp3+ TFH cells is not well understood, and their precise role in vivo has not been previously analyzed using a knockout mouse model. In this proposal, we propose to develop a novel mouse model where we will be able to genetically dissect out Foxp3+ TFH cells from the immune response for the first time. Using two different mutant mouse lines, including a newly developed mouse model we have generated, we will produce bone marrow chimeras (BMCs) where TFH and conventional (Treg-derived) TFR (cTFR) cells develop normally but Foxp3+ TFH cells cannot develop. Thus, we can use these mice to probe the development of high affinity Abs in the absence of Foxp3+ TFH cells. This model system can clarify whether Foxp3+ TFH cells have a very different function from cTFR cells in the GC and whether the helper activity of TFR cells for the Ab response in some immune responses is due to cTFR or Foxp3+ TFH cells or both types of cells. IMPACT: this study will generate an innovative mouse model of Foxp3+ TFH deficiency and will validate a new experimental system for analyzing Foxp3+ TFH cells. This work will also provide new information about the regulation of protective Abs and allergic IgE. Our data will hopefully lead to new targets for intervention in allergic and autoimmune disease and new approaches to augmenting protective Ab responses.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most common cancer predisposition syndromes, affecting approximately 1 in 2500 individuals worldwide. It is caused by pathogenic variants or deletions of the NF1 tumor suppressor gene resulting in Ras pathway hyperactivation. A hallmark feature of NF1 is the development of histologically benign peripheral nerve sheath tumors (PNST) called plexiform neurofibromas (PNF). While benign, the lifetime risk of these pre-existing neurofibroma undergoing malignant transformation to a highly aggressive sarcoma called a malignant peripheral nerve sheath tumor (MPNST) is 8-16%. The progression of PNF to MPNST typically occurs with little to no warning and clinical features concerning for malignancy often manifest after transformation has already occurred. The development of MPNST from pre-existing neurofibroma often proceeds through intermediate lesions known as atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP). However, not all neurofibroma will progress to MPNST and there are currently no clinically validated biomarkers capable of accurately identifying lesions at a high risk of undergoing malignant transformation. Risk assessment and therapeutic stratification of NF1-PNST is associated with several challenges as these tumors can exhibit significant intratumoral heterogeneity and diverse trajectories. During biopsy, sampling bias and the location of tumors in anatomically complex regions can hinder capture of the full spectrum of histopathological features. Current imaging methodologies also have limitations. On both MRI and FDG-PET scan, it challenging to definitively distinguish between benign and malignant tumors, particularly in cases of intermediary lesions or those actively transforming. These challenges underscore the need for diagnostic tools. We have identified DLK1 as a biomarker that holds potential promise in the setting of NF1-PNST. In collaboration with the Indiana Biosciences Research Institute (IBRI) and the Indiana Institute for Biomedical Imaging Sciences (IIBIS), we propose to build upon this work by undertaking a series of experiments to comprehensively elucidate the role of DLK1 in MPNST tumorigenesis and therapeutic sensitivity. We will extend these studies by developing and validating a novel DLK1-targeted diagnostic tools comprised of tissue- and molecular imaging-based approaches. Our overarching goal for the studies proposed in this application is to increase mechanistic DLK1 facilitated tumor progression and the development of clinical-grade DLK1- targeted diagnostic tools that can proceed immediately to clinical trial for further evaluation.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Evolution is one of the most powerful forces influencing the success and failure of life. Successful adaptation to one’s environment dictates the survivability of one’s genetic lineage. This is especially true for pathogenic bacteria, which must adapt to many stresses to successfully colonize and infect their host, replicate, and spread to a new host. Despite its importance, there is a fundamental gap in our understanding of how evolution influences bacterial pathogenesis. This proposal’s objective is to use an experimental evolution approach to determine the effects of evolution on the pathogenesis of the bacteria Klebsiella pneumoniae. K. pneumoniae frequently colonizes the gut, where it predominantly behaves as a commensal; however, gut colonization is the primary risk factor for K. pneumoniae disease and colonizing strains cause at least 80% of infections in colonized individuals. Thus, the gut is an important reservoir for infectious K. pneumoniae, which begs the question: how does evolution impact K. pneumoniae gut colonization and infection? This question is of high public health importance, as the prevalence of multi-drug-resistant K. pneumoniae and hypervirulent K. pneumoniae strains increases. Moreover, these strains are converging into dangerous multi-drug resistant, hypervirulent variants of K. pneumoniae. This necessitates a deeper understanding of K. pneumoniae gut colonization and infection. The central hypothesis of this proposal is that measurable, repeatable evolutionary events will enhance Kp gut fitness and modulate fitness during infection in a microbiome-dependent manner. We will test this hypothesis using two approaches: 1) we will assay K. pneumoniae evolution in the gut using a replay experiment; 2) Measure the impact of gut-derived mutations on K. pneumoniae pathogenesis. Using this approach, we will address the following questions: 1) does gut microbial community structure drive evolutionary outcomes?, 2) are K. pneumoniae strains experimentally evolved in the gut are fitter than their ancestors?, 3) does evolution in the gut enhance or restrict the ability of K. pneumoniae to colonize a novel host?, 4) does serial passage in the gut lead to reduced fitness during infection? The work in this proposal is innovative, as it requires a multidisciplinary approach to integrate experimental evolution with model systems that are directly relevant to human health. Completing this work will have a sustained positive impact through the identification and characterization of the mechanisms that underpin K. pneumoniae success in the gut and their impact on infection. This will help guide the development of decolonization interventions to reduce the risk of infection in individuals colonized by K. pneumoniae and potentially other opportunistic gut colonizers.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Each year there is an estimated eight million deaths globally that are attributed to sepsis. Sepsis is one of the leading causes of death in the pediatric population. When children die it is often from refractory shock and development of multi-organ failure. A key driver of this refractory shock is vascular dysfunction. Nitrosative stress has been linked to the pathophysiology of sepsis and is associated with this vascular dysfunction. However, the role of nitrogen oxides is incompletely understood in sepsis. There is a need to define the role of nitrogen oxides to identify new and effective therapeutic targets. S-nitrosothiols are endogenous nitrogen oxides that are exquisitely bioactive in vascular physiology. Many circulating S-nitrosylated proteins have established physiological roles. In addition, certain low-mass S-nitrosothiols have important physiologic roles and have been recently demonstrated to be stored and released from extracellular vesicles (EVs). In adults S-nitrosothiol levels are high when measured ex-vivo in sepsis. Unfortunately, due to their lability, measurement can be very difficult, thus limiting clinical utility. Our team has recently designed and validated a device that allows for non-invasive measurement of tissue S-nitrosothiols in-vivo. Our objective is to define the role of S-nitrosothiols in blood and EVs and to establish their relationships in sepsis. Our hypothesis is that circulating concentrations of S- nitrosothiols, including those in EVs, are increased in sepsis and that these high levels are associated with worse outcomes. My long-term career goal is to develop a research portfolio studying the biology of these molecules and to leverage this understanding to develop new therapies for sepsis. This K08 proposal summarizes a 5-year program of mentored support tied to a research project to better determine the roles of S-nitrosylation signaling in sepsis. Our specific aims for this project are to: (1) test the hypothesis that EV cargo is enriched with S- nitrosothiols in a murine model of sepsis and to identify novel S-nitrosylated proteins associated with sepsis- related pathways and (2) test the hypothesis that S-nitrosothiols are elevated in EV cargo from pediatric patients with sepsis, and their levels correlate with device-based measurements and predict clinical outcomes. Through my career development plan and ongoing support and education from my mentors, I will develop expertise in a) bioinformatics and proteomics, b) mouse husbandry, and c) EV biology and research techniques. Together the research and career development aims of this proposal will provide me with the necessary skills and education to compete for additional funding as an independent investigator. Specifically, I plan to submit for an R01 application through the NHLBI in year 5 of this career development award period. This proposal will focus on investigating the mechanistic underpinnings for the differentially expressed S-nitrosothiols contained in EVs. Overall, this proposal is an important first step in establishing my career as an independent investigator with a focus on pediatric sepsis.

NIH Research Projects · FY 2026 · 2026-03

This research proposal aims to decode the structural and molecular architecture of centriolar plaques (CPs), a non-centrosomal microtubule organizing center, in the context of atypical eukaryotic cell division. Using expansion microscopy (U-ExM), we will map CP composition and dynamics with high resolution investigating their roles in MTOC formation, cell polarity, and organelle segregation during division. Our approach integrates U-ExM with functional analyses, leveraging CRISPR-Cas9 technology to generate inducible knockdown cell lines. This strategy will reveal the localizations and roles of key CP components, including taxon-specific and conserved proteins, in supporting nuclear division and cellular organization. By advancing our understanding of CP architecture and function, this work will provide transformative insights into conserved and divergent principles of eukaryotic cell division, offering a comparative framework to explore cellular diversity across eukaryotes.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Peptides are an attractive scaffold for therapeutic development due to their unique ability to combine desirable features of both small molecules and larger, protein-based biologics. Like small molecules, peptides are synthetically accessible and can penetrate tissues effectively, yet they offer the superior binding affinity and specificity typical of biologics. Another key advantage of peptides lies in the availability of powerful screening technologies, such as phage display, which enables the rapid screening of vast peptide libraries to identify novel ligands for a chosen target. However, phage display libraries are traditionally limited to the 20 natural amino acids, which lack useful chemical functionalities found in non-ribosomal peptides and synthetic pharmaceuticals. As a result, the full potential of phage display in therapeutic peptide discovery remains underutilized. The overarching goals of my research are: (1) to develop synthetic and chemical biology approaches to expand the chemical diversity of phage display libraries, thereby improving their utility in early-stage drug discovery, and (2) to apply these expanded libraries to identify novel antimicrobial peptides. With this MIRA application, we seek to accomplish these goals by pursuing two interrelated research directions. Direction 1 focuses on inhibitor discovery using a new chemically and genetically augmented phage display platform. In preliminary studies, we developed a novel approach to introduce diverse chemical moieties into phage-displayed peptides by combining unnatural amino acid (uAA) mutagenesis with chemical post-translational modification. Over the next five years, we will use this strategy to produce peptide libraries containing, for example, reactive chemical warheads and metal-chelating groups, granting access to highly diverse libraries with unexplored chemical space. We will evaluate these expanded libraries for their ability to produce potent and selective inhibitors, with an initial focus on enzymes from multidrug-resistant Acinetobacter baumannii. This work will establish key principles for implementing this nascent technology for de novo inhibitor discovery and provide first-in-class inhibitors for bacterial enzymes of significant medical concern. Direction 2 focuses on expanding our repertoire of cysteine- reactive uAAs to produce cyclic peptides with unique molecular architectures. Cyclic peptides offer several advantages over their linear counterparts, but current methods for producing phage-displayed cyclic peptide libraries are technically challenging and/or limited in scope. Encouraged by strong preliminary data, we will develop two entirely new classes of uAAs, to produce ribosomally synthesized bicyclic and backbone-to-side- chain cyclic peptides. This work will provide access to unique cyclic peptide libraries that are not accessible with existing phage display technology. Moreover, as we push the limits of in vivo protein synthesis, incidental discoveries will likely offer new insights into the fundamental mechanisms of gene translation. Collectively, the proposed work will greatly expand the capabilities of phage display technology and accelerate the discovery of new peptides with broad research, diagnostic, and therapeutic applications.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Subjective cognitive decline (SCD), or self-reported persistent changes in cognitive capacity without the presence of objective cognitive impairments, is regarded as the first manifestation of preclinical or asymptomatic Alzheimer’s disease (AD) – falling between normal cognition and Mild Cognitive Impairment (MCI). Although SCD has potential to be a point of intervention for future clinical trials for disease modifying treatments for AD, the heterogenous nature of its etiology and cognitive trajectory requires new methods to better characterize this group if they are to have prognostic value in clinical trials. We have previously shown that short-term practice effects (STPE) are markers of diagnosis, clinical progression, and response to treatment in MCI and AD, though STPE as a predictive tool in SCD has been largely unexplored. An opportunity therefore exists to examine the benefit of using STPE to predict future change in cognition with greater specificity in a less symptomatic condition along the AD continuum. The principal objectives of this new application are to show that individuals with SCD possess smaller STPE than their cognitively normal peers (Specific Aim 1), and that these STPE are related to plasma biomarkers of AD (Specific Aim 2). This proposal will also investigate whether STPE are related to cognitive change and amyloid progression over 24 months (Specific Aim 3). Such findings in SCD would extend our previous work on STPE in symptomatic AD populations. In addition to practice effects being mostly unexamined in SCD, another innovative aspect of this proposal includes our use of a plasma biomarker for phosphorylated tau (pTau-217). Although pTau-217 has emerged as the superior biomarker for amyloid positivity and early prediction of AD, few studies of pTau-217 have been undertaken in SCD – especially longitudinally – and none have examined the relationship to practice effects. Further, to date, the literature on practice effects has been primarily conducted in Caucasian populations, whereas we are proposing to enrich our study sample with a broader racial/ethnic representation to ensure that the primary results will generalize to a more representative sample of the U.S. population. By achieving the aims of this proposal, we foresee multiple benefits. This work could better inform individual patients with SCD about their likelihood of future cognitive changes and disease progression. Additionally, should a combination of STPE and plasma biomarker assessment lead to more precise prediction of cognitive trajectories, SCD could become an ideal condition to consider for clinical trials of disease modifying treatments for MCI and AD. Given the clinical benefits that STPE may possess for diagnosis and prognosis of subjective cognitive decline and cognitive disorders in late life, this project is consistent with the mission of the National Institute on Aging.

NIH Research Projects · FY 2026 · 2026-03

Project Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent cause of liver disease worldwide. Liver fibrosis is a critical feature of MASLD progression, particularly in the stage of metabolic dysfunction-associated steatohepatitis (MASH). However, no effective treatment for liver fibrosis is currently available. Therefore, understanding the pathogenesis of hepatic fibrosis is essential for developing effective therapeutics. Hepatic fibrosis is an aberrant wound-healing process characterized by excessive extracellular matrix deposition. Multiple liver cell types contribute to hepatic fibrogenesis, including hepatocytes, hepatic stellate cells (HSCs), and hepatic macrophages. Among them, HSCs are the primary contributors to extracellular matrix accumulation, a hallmark of hepatic fibrosis. Sestrin 3 (Sesn3) belongs to a three-member protein family that shares three unique domain structures distinct from other proteins in the entire proteome. While sestrins have been implicated in MASH, their precise mechanisms remain incompletely understood. Our preliminary data suggest that Sesn3 is a critical regulator against hepatic fibrosis. Deletion of Sesn3 in HSCs exacerbated hepatic fibrosis in mice in response to an MASH diet whereas HSC-specific Sesn3 transgenic mice were protected from fibrosis development. Mechanistically, we Sesn3-Yap/Wwtr1 regulatory axis in hepatic fibrosis. In this application, we will characterize the function of Sesn3 and illustrate the novel Sesn3-Yap/Wwtr1 axis in HSCs during liver fibrosis development. The proposed research in this application will further elucidate the underlying mechanisms and demonstrate the translational potential of Sesn3 as a promising therapeutic target for hepatic fibrosis.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Insulin, central to the hormonal regulation of metabolism, is foundational to the management of Type 1 diabetes (T1D). This MPI application focuses on (a) ultra-stable single-chain insulin (SCI) analogs as probes of structure- activity relationships and their implications for design of (b) a novel class of glucose-responsive insulin analogs (GRIs). The latter would be transformational to mitigate the hypoglycemic risk of insulin therapy in T1D. Our Approach builds on respective cryo-EM-based structures of (i) an insulin fibril and (ii) signaling complexes between the hormone and the insulin receptor (IR). Each class of structures highlights the importance of conformational change. On the one hand, the major barrier to the stability of insulin above room temperature is posed by fibrillation, conformational conversion to a cross-β assembly (amyloid). On the other hand, partial unfolding of the B chain in the hormone-IR complex triggers receptor reorganization to achieve an active signaling conformation. The connecting (C) domain of SCIs provides a “molecular ruler” to probe these respective mechanisms of conformational change, enabled by analogs of successive C-domain length. Aim 1 seeks to resolve fundamental discrepancies between two recent 3D models of an insulin fibril. Decisive tests will be provided by residue-specific photo-cross-linking and 13C-directed solid-state NMR. Aim 2 investigates why foreshortened SCIs are intrinsically refractory to fibrillation: we hypothesize that a “sweet spot” exists in C-domain length: too short to permit cross-β assembly, sufficiently long to enable receptor binding and activation. Selective photo-reactive residues and 13C labels will be inserted by chemical protein synthesis. Cryo- EM structures will be sought of representative active SCI-IR ectodomain complexes and threshold SCI fibrils. Aim 3 re-conceptualizes the chain topology of an SCI as a platform for GRI design. Motivated by the profound clinical significance of hypoglycemia as a complication of insulin therapy, we envision a novel class of GRIs based on a glucose-dependent switch between an insulin antagonist (under hypoglycemic conditions) and an insulin agonist (under hyperglycemic conditions). This mechanism was anticipated in our studies of a fructose- responsive insulin prototype (FRI; Chen, Y.-S., et al. Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation. PNAS 118(3):e210351818 (2021)); see also a concurrent Commentary (Blundell, T.L. PNAS 118(33):e2111313118 (2021)). Here, we extend this strategy from FRI to GRI via a chemical glucose sensor. Remarkably, the proposed antagonist-agonist switch has been visualized in cryo-EM structures depicting glucose-dependent activation of a GRI-IR ectodomain complex and functionally validated in a rat model of T1D. To our knowledge, this scheme is unprecedented in the GRI field. Our Aims thus integrate basic and translational perspectives: ultra-stable, fibrillation-resistant SCIs would enhance insulin access in the face of an emerging diabetes pandemic (Weiss, M.A. Lancet Diabetes Endocrin. 11:307-9 (2023)) whereas GRIs promise to fundamentally transform the safety and efficacy of insulin therapy.

NIH Research Projects · FY 2026 · 2026-02

Alzheimer’s disease (AD) is a rapidly growing and serious worldwide malady, which is currently the most common cause of dementia in patients of advanced age. A major contributor to the brain pathology that is observed in AD patients is neuroinflammation, of which innate immunity plays a critical role. One component of the innate immune response that we have found contributes to AD is the MR1/MAIT cell axis. MR1 is a major histocompatibility complex class I-like molecule that is recognized by an invariant T cell subpopulation called, “mucosal-associated invariant T (MAIT) cells”. Notably, we have reported the presence of MAIT cell in the normal mouse brain. MAIT cells are innate-like T cells that have highly pathogenic roles in several different disease states, including some CNS disorders, via their production of the highly proinflammatory cytokine, IL-17A. We have detected increased MR1 expression in the temporal cortex of both AD patients and 8-month-old 5XFAD (AD model) mice and in their brain microglia as well. In fact, those microglia closer to and touching Aβ plaques have higher levels of MR1 than those further away and not touching. Moreover, we have found that there is a significantly greater number of MAIT cells in the brains and livers of 5XFAD vs. wildtype mice as they age. Importantly, crossing MR1-deficient mice (which have neither MR1 nor MAIT cells) onto the 5XFAD background, results in significantly delayed Aβ plaque development in the temporal cortex and hippocampus as compared to normal 5XFAD mice. Considering the variety of studies that have reported the substantial disease in AD patients and the various AD mouse models that have been studied to date, along with the associated neuroinflammation/neuroimmunopathology in the brain, we are focused on advancing our understanding the role of MR1 expression and MAIT cells in AD pathology development, using our preliminary data as a springboard to that end. Our hypothesis is that MAIT cell recognition of microglial and/or astrocyte MR1 results in MAIT cell production of IL-17A. This critically contributes to AD pathology upon the infiltration and/or proliferation of MAIT cells in the brain, resulting in significant neuroinflammation. To address this hypothesis, we have proposed the following three Specific Aims: 1. Determine the importance of brain microglial and astrocyte MR1 in AD pathology; 2. Define the contribution of IL-17A in MR1/MAIT cell-dependent AD development; 3. Determine the impact of MAIT cell numbers in AD neuroimmunopathology. These studies will allow us to determine mechanistic contributions of the MR1/MAIT cell axis in AD development in more detail, using both mouse models and AD patient tissue samples. This work could lead to the development of novel therapeutic approaches that target the MR1/MAIT cell axis in AD.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The purpose of the 7th World Parkinson Congress (WPC 2026) is to address a continued need for worldwide dialogue on the multifaceted problems of Parkinson’s Disease (PD) and to formulate and propose effective solutions, including new approaches to research and better models of care for people with PD (PWP). The WPC 2026, to be held from May 24 – 27, 2026 in Phoenix, Arizona, is the only international meeting in the field of PD that brings the whole PD community together for high-level scientific and lay sessions. Delegates at the meeting represent neuroscientists, physician-researchers, physicians, PWP, care partners, NPs, RNs, PTs, OTs, SLPs, SWs, and more from around 70 countries. The four-day program highlights advancements in the science of PD and models of care for PWP. Allowing researchers (basic, translational and clinical) the opportunity to exchange data on scientific advancements across different areas of science to help them explore and discuss new ideas and build collaborations they might otherwise not have considered. Including junior investigators in this important meeting offers interaction between early-stage and established leaders supporting the next generation of scientists. Inspiring those who are new to the PD field will help them to stay motivated and dedicated to ending PD. Broad support and involvement from the PD community (over 100 partnering organizations from 40 countries) shows that the WPC is the right venue for these multiple stakeholders to meet and build collaborations. Cross-pollination of experts researching and treating PD along with those living with the disease will spur new innovative research, identify potential solutions to unmet needs, and advance therapies for people with PD. More than 60 committee members have designed an elaborate scientific program with 160 speakers from all areas of the PD community with sessions designed to maximize learning potential and dialogue, including large and medium-sized as well as incredibly intimate round-table sessions with just 12 participants discussing a topic in depth. The morning plenaries will look at the Biological definition and staging of PD: Use and Implications for care and research; Current state of the disease- modifying therapy (DMT) pipeline for Parkinson’s disease; and Exercise and PD. Plenaries set the stage for discussion in later sessions covering a wide range of topics such as: Organelle (Dys)function and Crosstalk in PD; Subtypes of PD and their Implications; Research Advances in GBA1- and LRRK2-associated PD; Artificial Intelligence, Big Data, and Digital Devices in PD Care; Immunity and inflammation in PD; The science of boosting physical and cognitive health in PDs; The Gut-Brain Axis in PD; Therapies for Advanced Disease and more. At the end of each day, Controversy sessions bring the delegates together for lively debates. There will be both Scientific and Living with PD posters highlighted in Poster sessions and tours to maximize interaction among the delegates. Authors of the 12 most outstanding posters will be invited to present oral ʻHot Topicsʼ talks to the plenary audience, to further promote scientific dialogue, and foster more collaborations.

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT Immune-mediated protection against malaria, termed clinical immunity, develops over many years of repeated exposure to Plasmodium, requires continuous exposure to Plasmodium, and correlates with circulating titers of Plasmodium-specific antibodies. Why Plasmodium infections fail to induce long-lasting protection following one or few infections, thereby contributing to the chronic pathogenesis of malaria, remains unknown. The objective of this proposal is to determine the effect of Plasmodium infections on germinal center (GC) B cells and bone marrow (BM) homeostasis towards inefficient generation of long-lived plasma cells (LLPCs). Many infections and vaccines elicit long-lasting antibody titers after one or just a few exposures. The half-lives of circulating antibody titers for viral antigens following infection or vaccination have been shown to range from 10 years to >300 years. In contrast, half-lives of circulating Plasmodium-specific antibody titers are reported to be in the range of several days. Long-term maintenance of circulating antibody titers comes from GC-derived plasma cells (PCs) that migrate to the BM where they receive survival signals and become LLPCs. To investigate why Plasmodium infection induces short antibody half-lives, we compared spleen GC responses and development of BM LLPCs in mice following infection with Plasmodium yoelii 17XNL (Py) to mice immunized systemically with NP-CGG plus the adjuvant AddaVax. Our preliminary data demonstrate that despite the induction of robust spleen GC responses during Py infection, Py-induced GC B cells are inefficient at generating LLPCs in the spleen and BM and that Py-specific IgG-secreting cells in the spleen and BM exhibit decreased IgG production and affinity. These data suggest Py infections exhibit dysregulated humoral immunity by impacting the functional programming of spleen GC B cells or PCs. Py-induced splenic PCs were able to migrate towards the BM homing cytokine CXCL12, suggesting inefficient generation of LLPCs following Py infection could be attributed to functional deficiencies in the BM microenvironment that support engraftment and survival of LLPCs. Consistent with this possibility, there were decreases in the number of BM cells that provide recruitment signals for PCs and survival signals for LLPCs during Py infection that was associated with an increase in multiple cytokines in the BM, including IFN-γ. Blocking IFN-γR signaling during Py infection partially prevented the loss of BM cells and increased BM PC numbers. These observations collectively lead to the hypothesis that failure to engender LLPCs following Plasmodium infection is attributed to intrinsic differences in spleen GC B cell programming that affect PC functionality and changes in the BM microenvironment that fail to support LLPCs. The hypothesis will be tested through the following aims. Aim 1. Identify the functional deficits in spleen GC B cells and PCs following Py infection responsible for inefficient generation and function of LLPCs. Aim 2. Define the cellular and molecular mechanisms by which Py alters the BM microenvironment to impede the development of LLPCs.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract Vascular contributions to cognitive impairment and dementia (VCID) are a significant yet underexplored factor in dementia pathology, frequently coexisting with Alzheimer’s disease (AD). While pericytes, astrocytes, and microglia have been studied for their roles in cerebrovascular damage, platelets—typically found beyond the blood-brain barrier—may also contribute to vascular dysfunction. Platelets drive endothelial injury through pro- inflammatory signaling, extracellular matrix degradation, and thrombotic activity, yet their role in cerebrovascular decline remains unclear. Given their accessibility and known involvement in vascular disease, targeting platelets may provide a novel therapeutic avenue for VCID, an area currently lacking effective treatments. This proposal aims to investigate platelet-mediated mechanisms of vascular injury in VCID and determine whether inhibiting platelet surface receptor function can mitigate disease progression. We hypothesize that platelets adopt a hyperactive, pro-inflammatory phenotype that exacerbates cerebrovascular dysfunction and that inhibiting platelet glycoprotein VI (GPVI) signaling will alleviate these effects. To test this, we will assess platelet activation and vascular interactions over time in two VCID mouse models: diet-induced hyperhomocysteinemia (HHcy) and amyloidogenic Tg2576 mice. Using flow cytometry, multiphoton imaging, and histological analyses, we will characterize platelet activation states, surface receptor expression, and their infiltration into cerebrovascular structures. Additionally, we will determine whether GPVI depletion reduces platelet-driven vascular damage and inflammation, thereby improving cognitive and physiological outcomes. The successful completion of these aims will provide crucial insights into the overlooked contributions of platelets to VCID pathology and establish their potential as therapeutic targets. Furthermore, this project will enhance my technical expertise in neurovascular imaging, histology, RNAseq, and mouse modeling of neurovascular disease while contributing to my professional development as an independent researcher. With the resources available at Indiana University – Indianapolis, including the Alzheimer’s Disease Research Center and mentorship from Dr. Wilcock, this proposal will advance both scientific knowledge and my career trajectory in dementia-related research.