NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases Grants

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY. Antibody and antibody fusion protein therapies targeting adaptive immune cells have shown variable inter-subject levels of success at halting autoimmune destruction of the insulin-producing pancreatic β-cells in individuals recently diagnosed with Type 1 Diabetes (T1D). Responsiveness to many antibody therapies vary in other autoimmune diseases and cancer according to Fc gamma receptor (FcγR) variants impacting a patient’s capacity for Fc-mediated mechanisms of action (Fc-MoA) such as antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Indeed, pharmacodynamics of low-dose α-thymocyte globulin (LD-ATG) and clinical efficacy of rituximab (α-CD20) have been demonstrated to be affected by FcγR variants in the context of transplantation or rheumatoid arthritis and lymphoma, respectively. However, whether responsiveness to these therapies in individuals with T1D are similarly affected by FcγR-associated variants remains unknown. Therefore, I hypothesize that FcγR-associated variants may influence efficacy of therapeutic antibodies with FcγR-binding capabilities in recent-onset T1D via regulation of ADCC and ADCP. Indeed, I have identified a significant association between an FCGR2B expression QTL (eQTL) and quantitative metabolic response (QR) in the LD-ATG trial (TN19). The objectives of my proposed studies are to build on this finding by identifying genetic variants in FcγR loci that associate with therapeutic efficacy in additional completed T1D immunotherapy trials and to evaluate the consequences of modified FcγR expression and/or function on Fc-MoA. In Aim 1, I will perform quantitative trait locus (QTL) analysis of FcγR-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) versus treatment efficacy and target cell depletion in TrialNet (TN) and Immune Tolerance Network (ITN) studies of native Fc-containing antibody therapeutics in recent-onset T1D. I will analyze associations between genotype microarray, clinical endpoints, and flow cytometry data from the rituximab (TN05) and alefacept (Inducing Remission in T1D With Alefacept [T1DAL], ITN) trials. In Aim 2, I will determine impacts of FcγR-associated variants on cell type-specific FcγR protein expression and regulation of Fc-MoA of therapeutic antibodies for T1D. Here, I will characterize human whole blood samples by flow cytometry to evaluate associations between cell type-specific FcγR protein expression and previously defined whole blood eQTLs, with a focus on the LD- ATG response-associated FCGR2B variant. I will also employ rapid and fluorometric ADCC (RFADCC) assays to measure LD-ATG- and rituximab-mediated ADCC and ADCP induction by genotype-selected natural killer (NK) cell and monocyte effectors and T cell or B cell targets, respectively. I expect my findings will support a precision medicine approach to identify individuals with or at-risk for T1D who are likely to respond positively to native Fc-containing immunotherapies, as well as to guide dose optimization strategies for non-responders.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY 2025 Rachmiel Levine-Arthur Riggs Diabetes Research Symposium November 14-17, 2025, Westin Pasadena, Pasadena, CA Despite the significant knowledge obtained and the progress made in the treatment of diabetes over the last 50 years since the discovery of insulin, translation of this understanding to the clinic, and implementation of acceptable standards of care for diabetics has been suboptimal. In view of the rapidly growing worldwide diabetes epidemic - the disease affected 22.3 million people in the USA and 371 million people worldwide in 2012, and is expected to double by 2030 if current trends hold - it is imperative to enhance current interactions among investigators. This is to foster new collaborations, and pool knowledge and resources so that the cellular and molecular mechanisms responsible for the disease and its complications can be determined, and novel therapeutic strategies developed that will effectively prevent, delay, and even cure diabetes. The 2025 Rachmiel Levine-Arthur Riggs Diabetes Research Symposium, to be held from November 14-17, 2025 at The Westin in Pasadena, California, will continue to meet the growing demand to keep researchers, clinicians and trainees abreast of the latest developments in diabetes- and endocrine-related research. The Symposium is organized by the City of Hope’s Arthur Riggs Diabetes and Metabolism Research Institute (AR-DMRI) and is expected to attract over 250 attendees from both the U.S. and abroad with diverse academic backgrounds including, endocrinologists, diabetologists, islet biologists, stem cell and gene transfer scientists, transplant scientists, immunologists, cell biologists, young investigators in all these areas, and health care professionals who manage individuals with diabetes. The four-day meeting will offer presentations from over 60 experts in the field of type 1 diabetes and islet cell biology. The meeting will consist of introductory lectures and plenary sessions that will each conclude with a panel discussion. In addition, the meeting will offer a debate session, oral presentations from junior investigators and trainees, and a poster session for both junior and established investigators to present new and exciting data. The Symposium provides an important venue for investigators to present their data to an audience of national and international experts, helping to foster the career growth of junior investigators.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

SUMMARY Investigating Syndecan-1 in Hepcidin Regulation and Iron Metabolism. Iron is an essential trace mineral, involved in many vital cellular and organismal functions. Organismal iron content is controlled by dietary absorption, iron partitioning in erythrocytes, iron recycling by macrophages and iron storage in hepatocytes. The hormone, hepcidin is a master regulator of systemic iron content as it negatively regulates ferroportin, the primary cellular iron exporter mediating iron flow from enterocytes, macrophages and hepatocytes into the circulation. We have shown that heparan sulfate is key component of hepcidin regulation. Inhibition of heparan sulfate biosynthesis in hepatoma cells and in mice reduces baseline, BMP6-stimulated, and IL6-stimulated hepcidin expression and worsens the pathophysiology characteristic of anemia of inflammation. We have now identified syndecan-1 as the primary HSPG regulating liver hepcidin expression based on genetic and pharmacological inactivation of syndecan-1 expression in human and mouse hepatoma cells. Our findings imply that endogenous hepatic syndecan-1 serves as a template to support signaling complexes regulating hepcidin expression and iron metabolism. We propose to extend our studies to human hepatocytes; to determine the mechanism underlying the requirement for Sdc1-mediated regulation of hepcidin expression; and to exploit this information to develop strategies to treat disorders characterized by iron overloading. To achieve these goals, we will (i) Examine the role of syndecan-1 in driving basal and iron- inducible hepcidin expression in human hepatocytes; (ii) Determine the mechanism of syndecan-1 regulation of hepcidin expression and (iii) Evaluate the efficacy of genetic and pharmacological syndecan-1 targeting to correct iron dyshomeostasis in iron-loading disease models. The overarching goal of this proposal is to evaluate the relationship of syndecan-1 structure to iron metabolism, with the long-range goal of defining new potential targets to reduce the risk of iron-loading disorders, such as anemia of inflammation.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

If there is no change, enter No changes to the abstract or NONE. Adipocyte dyfuntion results in reduced BAT thermogenesis, low-grade chronic inflammation, fatty liver, and systemic insulin resistance. Still poorly understood are the mechanisms that trigger diet-induced obesity-associated adipocyte dysfunction. Our studies have identified that the transcription factor, interferon regulatory factor 8 (IRF8) is expressed constitutively in adipocytes of mice fed a low fat diet and when mice are fed a high fat diet (HFD) IRF8 expression is increased in white adipose tissue and brown adipose tissue adipocytes. Our preliminary studies position adipocyte IRF8 as an important transiption factor regulating brown and white adipocyte gene expression and metabolism, insulin resistance and diet-induced obesity and associated metabolic complications. Our goal is to ultimately define the specific role of IRF8 in white and brown adipocytes on adipocyte and systemic metabolism in mice fed a low fat and high fat diet to induce diet-induced obesity

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Lipid Droplets (LDs) are rapidly emerging as critical adaptive organelles at the nexus of lipid metabolism and human disease. The 10th FASEB Summer Research Conference on "Lipid Droplets" will delve into this rapidly evolving field. As the primary cellular lipid storage organelles, LDs serve as vital hubs of lipid metabolism, influencing energy storage, lipid signaling, membrane biogenesis, and lipotoxicity. Pathological LD accumulation is a hallmark of metabolic diseases including obesity, insulin resistance, diabetes, fatty liver disease, lipodystrophy, cancers, cardiovascular diseases, and neurodegeneration. The growing prevalence of metabolic disorders in the United States underscores urgency to mechanistically understand the molecular underpinnings of LD formation, growth, movement, and turnover. Understanding LD biology promises novel therapeutics and is thus of high interest to scientists in academic, pharmaceutical, and biotechnology sectors. This conference will take place from July 26 to 30, 2026, in Scottsdale, AZ, USA. It will co-locate with the FASEB SRC Phospholipids conference, and include three keynote addresses from lipid metabolism leaders: Dr. Hugo Bellen (Baylor College of Medicine, HHMI), Dr. Elina Ikonen (University of Helsinki), and Dr. Bruno Anthonny (CNRS). As the longest-running meeting solely focused on LD biology, it will feature a multi- disciplinary speaker line-up focused on leading-edge research in basic and clinical science. The conference format comprises eight sessions featuring talks by invited speakers, 15 short talks selected from submitted abstracts, two poster sessions (together with the FASEB SRC Phospholipid conference), a Career-Oriented Workshop, and Meet-the-Experts sessions. Its trainee-focused environment has been carefully crafted to foster interactions between trainees, early career investigators, and established researchers. Scientific sessions will span the entire spectrum of LD biology. Distinguished researchers will deliver talks spanning many approaches (biophysics, genetics, biochemistry, cell biology, physiology) and cutting-edge technologies (chemical biology tools, lipidomics, new imaging approaches) in a range of model systems (cultured cells, Drosophila, yeast, C. elegans, mice, humans). A primary aim of this conference is to nurture and empower the next generation of scientists. To that end, we seek funding to support the participation of 15 graduate students, postdoctoral fellows, and early career investigators. The conference's informal and trainee-oriented setting will provide numerous opportunities for planned and spontaneous informal interactions, affording young investigators the chance to present their work, obtain valuable feedback from leaders in the field, and receive career guidance. In closing, this conference stands as the pioneering international gathering dedicated exclusively to lipid droplet biology and its profound relevance to human diseases. It continues to serve as a unique and memorable forum for researchers to exchange ideas and share groundbreaking results.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract: Robust evidence supports the use of continuous glucose monitoring (CGM) to assess glycemic control and inform clinical decisions in adults with type 1 diabetes (T1D). The voluminous raw CGM data (glucose reading every few minutes) is summarized into 8 standard CGM metrics (e.g., time in range [TIR] defined as percent time with glucose readings between 70–180 mg/dl). However, recommended targets for each CGM metric (e.g., >70% TIR) are based on expert opinion and have not been evaluated empirically. To establish evidence-based goals of care in adults with T1D, our research will identify optimal CGM metric targets that minimize diabetes complications using causal machine learning models. The proposed work will leverage data from a contemporary (2016–2025) cohort of ~4000 adults with T1D from Kaiser Permanente Northern California (KPNC). Consistent with current T1D care guidelines, all analyses will be stratified into an older/high-risk group for whom clinical decisions typically prioritize short term safety (i.e., avoidance of hypoglycemia and diabetic ketoacidosis) and the remaining younger/healthier group for whom clinical decisions prioritize avoidance of acute metabolic events as well as long term microvascular and cardiovascular complications. In Aim 1, for each of the 8 standard CGM metrics included in the ambulatory glucose profile, we will identify optimal targets that are associated with the lowest risk of each of 4 complication categories (hypoglycemia, diabetic ketoacidosis, microvascular, and cardiovascular events) separately. To identify opportunities for quality improvement, and inform future guidelines and translational research, in Aim 2 we will assess the proportion of patients achieving the novel optimized CGM metric targets (calculated in Aim 1) as well as CGM metric targets recommended in the 2026 American Diabetes Association Standards of Care in Diabetes. Identifying CGM metric targets based on real-world evidence rather than expert opinion will lead to improved patient-centered care and quality of life and for adults with T1D.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

The mammalian liver is composed of parenchymal (hepatocytes) and non- parenchymal (endothelial, kupffer, cholangiocytes, stellate) cells organized into repetitive hexagonal arrays termed lobules. Within each lobule the hepatocytes are distributed from the portal triad (portal vein, hepatic artery, bile duct) at the six vertices of the hexagon and the central vein located at the centroid. The hepatocytes aligned within a lobule display functionally distinct metabolic properties and are generally divided into three zones, the periportal hepatocytes (zone 1), middle hepatocytes (zone 2) and the pericentral hepatocytes (zone 3). Many studies have further shown that the hepatocytes have distinct functions across the periportal to pericentral spatial axis across each individual lobule. One important liver metabolic function is gluconeogenesis that is a dynamically regulated process controlled by numerous hormones and metabolic inputs. During our investigation of the temporal and spatial regulation of gluconeogenesis, we observed that there is a distinct basal (fully fed) state of active gluconeogenesis restricted to periportal hepatocytes. Further investigation has revealed the presence of a novel subset of periportal hepatocytes (termed Dual-Modal hepatocytes) that express both gluconeogenic and lipogenic genes in the fed state, suggesting that these cells are naturally resistant to suppression of either gluconeogenic activity or gluconeogenic gene expression by insulin. These data provide the unexpected conclusion that normal livers have a unique subset of hepatocytes that remain gluconeogenic in the fed state and have the capacity to simultaneously express lipogenic genes and undergo de novo lipogenesis. These findings open the paradigm-shifting possibility that hepatic insulin resistance may not necessarily arise from an induction of cellular insulin resistance but alternatively from the expansion (proliferation) in the number of these pre-existing insulin-resistant hepatocytes. Using integrative physiologic approaches coupled with various single cell technologies coupled with stable isotope metabolic spatial imaging, we propose a series of studies to unravel the physiologic and pathophysiologic role of these Dual-Modal hepatocytes.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Rates of obesity have steadily increased in the US, with about 50% of Americans projected to be obese by 2030. Recent advances include GLP-1 peptides, such as semaglutide, approved in 2021 for adult obesity, and setmelanotide, approved in 2020 for early-onset syndromic obesity due to POMC and leptin receptor deficiency. However, setmelanotide is not sufficiently effective for MC4R haploinsufficiency or common dietary obesity, causes hyperpigmentation, and requires daily injections. GLP-1 therapies also show variable efficacy, with 23% of patients losing less than 5% of body weight after two years and up to 30% experiencing nausea. To improve the potency and specificity of MC4R peptide agonists like setmelanotide, we performed extensive structure-activity relationship work involving the synthesis and characterization of 426 new melanocortin peptides (MCs). This work led to discovery of MCs with 4X increased potency relative to setmelanotide, and with reduced hyperpigmentation. Also exciting, we recently discovered that MCs increase the dose-sensitivity to GLP-1s without increasing malaise or activity in the brain’s emesis center. This finding could help reduce well-known toxicity of GLP-1s, allowing more patients to benefit from GLP-1s. To realize cost-effective and facile PLGA microsphere encapsulation and delivery of the MCs and GLP-1s, we recently discovered an extremely simple, efficient, and generalizable water-based remote encapsulation method for peptides, involving short-term mixing of aqueous peptides and empty poly(lactic-co-glycolic acid) (PLGA) microspheres. In this R56 grant our team will further develop and optimize the remote-loading method for GLP-1s, while further advancing the mechanism of the rapid and spontaneous remote peptide loading based on peptide-polymer binding with or without additional excipients at physiological temperature. The new encapsulation method will allow for the combination of multiple formulations of sterile empty PLGA microspheres that encapsulate the peptide drugs to achieve constant drug release. We will determine the dosing of both single MC and MC/GLP-1 combinations in acute and chronic animal models of both genetic (MC4R+/-) and dietary obesity. For MCs we will use remote-loaded setmelanotide formulations already developed in the lab. We will evaluate pharmacokinetics of the remote-loaded GLP-1s to facilitate microsphere combination for constant peptide release and to test their release performance in vivo. Hence, this new drug delivery approach using MCs and their GLP-1 combinations could be useful for future treatments of a wide variety of forms of obesity.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

There is a decline in medical graduates choosing pediatric residency programs (National Resident Matching Program 2024 report) and a persistent and growing workforce crisis within Pediatric Nephrology. We are compelled to increase our efforts to mentor Pediatric Nephrology Fellows and recruit more pediatric residents into our field through improving the development and satisfaction of pediatric nephrology fellow trainees throughout their training. The Pediatric Nephrology Research Consortium (PNRC) Board created the PNRC Pediatric Nephrology Fellows Initiative in Spring 2024, led by Dr. Myda Khalid. American Society Pediatric Nephrology (ASPN) enthusiastically endorsed this work as it aligns with the goals of ASPN and the ASPN’s Workforce Committee. With the Spring 2026 Workshop, we aim to improve the development of trainees by offering an ASPN-PNRC Pediatric Nephrology (First-Year Fellows) Workshop. It will focus on clinical research skills development, career development and research and career mentorship. Following the workshop, the Fellows are invited to attend the PNRC meeting. The Consortium represents more than 95 pediatric nephrology sites across the United States and Canada. In this meeting, the Fellows will engage in the collaborative exchange of ideas and the formation of multi-centered research studies alongside their mentors and pediatric nephrologists. Finally, the Fellows then attend the 2026 Miami Pediatric Nephrology Seminar. The Miami Seminar gathers a diverse range of healthcare providers including adult and pediatric nephrologists, urologists, scientists and other allied health providers. The seminar offers a series of multidisciplinary discussions and features a Pediatric Nephrology Young Investigator’s showcase in which trainees are invited to present research work in oral presentation or poster format. This sequence of meetings gives the trainees many opportunities to establish relationships with mentors, to interact with faculty and participants to stimulate them in areas of research development and foster their interest in pediatric nephrology as an enduring career choice.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Despite the tremendous efforts in obesity research, pharmacological interventions that solely suppress appetite alone have proven largely ineffective in addressing this global health issue. Therefore, increasing energy expenditure has emerged as an alternative means to combat the obesity epidemic. Emerging evidence suggests that cold exposure is a promising approach to alleviate obesity and related metabolic disorders, but the neurobiological mechanisms mediating cold response remain poorly understood. In my pilot studies, I demonstrated that cold exposure evokes a profound activation of neurons in the posterior periventricular hypothalamic nucleus (PVp), most of which are GABAergic. I further showed that activation of GABAergic neurons in the PVp (GABAPVp neurons) increases both food intake and energy expenditure. Strikingly, repeated activations of these GABAPVp neurons resulted in improved glucose tolerance and insulin sensitivity, despite the fact that mice constantly ate more. Together, I developed a hypothesis that GABAPVp-originated neural circuits mediate metabolic benefits during cold exposure. The K99 phase will focus on unravelling the physiological relevance of cold-sensitive PVp neurons in energy and thermal homeostasis. I will use intersectional genetics to dissect the functional relevance of different PVp subsets on energy and thermal regulations during cold exposure. In addition, I will employ the GRIN lens calcium imaging system to monitor the response to cold exposure and feeding in individual GABAPVp neurons. During the R00 phase, I will utilize the techniques and the problem-solving experience I acquire from the K99 phase to identify the downstream targets that mediate the effects of GABAPVp neurons and the cold-sensor. I will combine the Cre-loxP, Flpo-Frt strategies and retrograde viral vectors to determine the contributions of the lateral periaqueductal gray (LPAG) and lateral parabrachial nucleus (LPBN) to energy and thermal homeostasis during cold exposure. I will also assess the effects of Kcnk2 in GABAPVp neurons on cold-sensing as well as energy and thermal balance. The K99 phase will provide an ideal training opportunity to equip me with essential techniques, knowledge, and problem-solving skills, which will prepare me for the R00 phase of research and growing into an independent researcher focusing on neural mechanisms of obesity and energy balance.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY We are organizing the third Gordon Research Conference (GRC) on the topic of the hypothalamus, scheduled to take place on August 16 - 21, 2026 at the Grand Summit Hotel at Sunday River, in Newry, Maine. This GRC will be held in conjunction with an associated Gordon Research Seminar (GRS) on August 15-16, 2026 at the same location. The overall objective of the Hypothalamus GRC is to bring together an interdisciplinary group of researchers to highlight the latest research on the role of hypothalamic cells and circuits in health and disease. Our program will have sessions on the role of the hypothalamus across diverse physiological and behavioral phenotypes in multiple model organisms. Our speakers and discussion leaders represent a group of scientists from a variety of scientific backgrounds and across all career stages who each study the structure and function of the hypothalamus at different levels of investigation. Furthermore, the addition of an associated Hypothalamus GRS will allow many more graduate students and postdoctoral scholars to share their work and meet each other, helping to support the next generation of scientists in our field. As for all GRCs, the guiding principle of this meeting will be the presentation of new, unpublished results with ample time for free, unencumbered discussion. Taken together, the Hypothalamus GRC and GRS will provide an extraordinary opportunity for researchers across many biological disciplines with a common interest in the hypothalamus to interact, share ideas, collaborate, and ultimately advance the field.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract Myelodysplastic syndromes (MDS) are a group of diverse malignant hematological disorders that originate from hematopoietic stem cells (HSCs). Increased levels of reactive oxygen species (ROS) and DNA damage are commonly detected in hematopoietic cells from MDS patients. An elevated level of ROS, generated from either endogenous or exogenous sources including oncogene activation, leads to loss of quiescence and self-renewal of HSCs. ROS-induced DNA damage speeds up the aging process of stem cells and contributes to the mutagenesis associated with cancer development. m6A RNA methylation plays a significant role in multiple biological processes by introducing another layer of post-transcriptional regulation of gene expression within cells. The goal of this project is to elucidate the significant role of ALKBH5-mediated epigenetic regulation in the maintenance of genomic stability in hematopoietic stem/progenitor cell (HSPCs) during oxidative stress, and how deregulation of ALKBH5 contributes to promotion of leukemic transformation of HSPCs in the initiation and development of MDS. We found that ROS significantly increased global m6A RNA methylation in human cell lines, and that the elevation of m6A mRNA methylation is required for rapidly repairing ROS-induced DNA lesions and preventing cell death. Interestingly, we found that ALKBH5, the m6A RNA demethylase, is responsible for ROS-induced elevation of m6A mRNA methylation. ROS induced post- translational modification of ALKBH5, and inhibited the demethylase activity of ALKBH5. We showed that forced expression of ALKBH5 inhibited ROS-induced m6A mRNA methylation and significantly delayed repair of ROS-induced DNA damage. Thus, we hypothesize that aberrant expression of ALKBH5 disrupts HSPC functions by negatively influencing genome integrity and survival of HSPCs, thereby contributing to leukemic transformation of HSPCs during the initiation and development of MDS. In this proposal, we will determine 1) the role and underlying mechanism of ALKBH5 in the maintenance of genomic stability in HSPCs in response to oxidative stress; 2) the effects of ALKBH5/Alkbh5 overexpression on the maintenance of mouse and human primary HSPCs during ROS stress in vivo; and 3) whether ALKBH5/Alkbh5 is required for the maintenance of pre-leukemic stem cells (pre-LSCs) in MDS. Our study will provide new insights into novel mechanisms of MDS development and epitranscriptional regulation of gene expression in HSPCs in response to oxidative stress. Additionally, our study will provide the first set of evidence to support a significant role of ALKBH5- mediated m6A mRNA demethylation in the maintenance of normal HSPCs and pre-leukemic stem cell (pre- LSCs).

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT Abnormal lipid and lipoprotein metabolism is mechanistically linked to many common diseases such as obesity, fatty liver, diabetes, cardiovascular disease (CVD), and neurodegenerative diseases. The Gordon Research Conference (GRC) on Lipoprotein Metabolism is recognized as a premier meeting for disseminating cutting-edge research, sparking collaborations, and fostering new paradigms in this fast-moving field. The 2026 GRC will continue this tradition of highlighting research excellence in various areas of lipid and lipoprotein metabolism. The conference, to be held in Waterville Valley, NH from June 2-7, will focus on important new developments in lipid and lipoprotein metabolism relevant to human disease. Oral presentations (in 9 integrated sessions) will highlight state-of-the-art scientific approaches, exploring molecular, structural and cell biological studies, model systems of metabolism, and preclinical and human studies of new therapeutic targets. The overarching goal is to bring together scientists from diverse research areas, career stages, and geographical locations who share a passion for discovering and applying new paradigms in lipid and lipoprotein metabolism to improve human health. The GRC will be preceded by the Gordon Research Seminar (GRS), a forum for trainees to present their research in a setting of mentorship and inspiration provided by peers and selected faculty in attendance. The First Aim of the 2026 GRC on Lipoprotein Metabolism is the communication of cutting-edge, unpublished science on lipoprotein metabolism. This includes 45 presentations in 9 oral sessions, each with an identified theme and a discussion leader who will facilitate dialogue and encourage participation by all attendees. Several of the oral sessions will feature short presentations by trainees and early career investigators, selected from submitted abstracts by a panel of established investigators. The roster of confirmed speakers is an impressive array of leading researchers from a range of career stages and represent the world’s best scientists in the area of lipid and lipoprotein metabolism. Our Second Aim is to achieve broad participation and engagement opportunities for all attendees. GRCs place high priority on the principles of safety and the creation of a welcoming environment. The 2026 GRC on Lipoprotein Metabolism has long-standing reputation as a safe and engaging meeting for all participants to share their unpublished results in a collegial manner. We expect this meeting to discuss the opportunities and challenges for emerging therapies for diseases such as CVD, obesity, diabetes, fatty liver disease, and Alzheimer’s and related dementias. Collectively, we expect the 2026 Gordon Research Conference (GRC) on Lipoprotein Metabolism to improve human health through promoting open dialogue, collaboration, and scientific innovation.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, with anemia as its most common and clinically consequential manifestation. Recent integrative genomic analyses have revealed that STAG2-mutant MDS represents the most erythropoietin (EPO)–refractory genetic subtype across IPSS-M risk categories, underscoring a critical unmet need to understand the molecular basis of erythroid failure in this disease. Our prior work demonstrated that loss of Stag2 disrupts erythroid differentiation and leads to elevated circulating EPO in vivo, indicating a state of profound EPO resistance. In newly accepted work, we show that Stag2-dependent chromatin accessibility enforces erythroid-specific GATA1 cistrome engagement, and that Stag2 loss leads to accessibility-driven retargeting of GATA1 toward megakaryocytic loci, thereby impairing erythroid output. The objective of this one year R56 bridge project is to advance a focused subset of aims by determining whether STAG2 dependent defects in erythroid differentiation and transcription factor engagement are functionally reversible. Specifically, this project will interrogate the impact of STAG2 loss and restoration on erythroid output, EPO responsiveness, and chromatin dependent GATA1 activity in vivo, and will establish a tractable experimental system to test the reversibility of these erythroid defects. These studies will provide critical mechanistic and feasibility data and will inform subsequent efforts to restore erythroid competence in STAG2 mutant MDS. Together, these studies will directly address the mechanistic basis of EPO resistance in STAG2-mutant MDS and provide critical feasibility and validation data to support a revised R01 focused on therapeutic restoration of erythroid function.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Advancing our understanding of human pancreatic diseases, especially pancreatitis and pancreatic cancer, requires the cooperative effort of a network of clinical centers of excellence and the regular meeting of thought leaders in the field. The course objectives for PancreasFest 2026 will enhance progress on meeting research priorities highlighted by the National Commission of Digestive Diseases. Specifically, we will 1) Critically review advancements in medical, endoscopic and surgical managements to pancreatic diseases; 2) Critically review acute and chronic pancreatitis and pancreas cancer clinical-translational research; 3) Discuss new emerging therapies for pancreatitis and pancreatic cancer, and facilitate a round table discussion on how to accelerate meaningful therapies for these highly disabling conditions. PancreasFest was first hosted at the University of Pittsburgh over 20 years ago, with the aim of creating a collaborative environment for learning and networking. In 2023, CAPER (Collaborative Alliance of Pancreatic Education & Research) became the organizing body for PancreasFest, and now the meeting rotates locations, but recognizing the importance of Pittsburgh in the founding of PancreasFest, it returns to Pittsburgh in each odd numbered year. For 2026, PancreasFest will be held for the first time on the University of Minnesota campus at the Graduate hotel. The hosting organization CAPER is a nonprofit devoted to enhancing the career development of junior physician scientists in the field of pancreatology. PF focuses exclusively on fostering translational multi-center programs for pancreatic disorders. Attendees of past meetings uniformly praise PancreasFest for fostering collaborative research and for its emphasis on the importance of a small conference focused on pancreatic disorders. Multiple clinical working groups have emerged over the years through PancreasFest that focus on areas of NIDDK interest. Approximately 250+ medical professionals from varied medical disciplines register for PancreasFest each year, including physicians and scientists interested in the pancreas: pancreatologists, endoscopists, surgeons, radiologists, pathologists, molecular biologists, pediatricians, geneticists, epidemiologists, statisticians, systems biologists, subspecialty medical professionals, and experts in biomarkers. We encourage attendance from new faculty and fellows to ensure that the next generation of pancreatic investigators works directly with and learns from senior researchers in the field. Key staff from the NIDDK are invited to provide scientific insights. PancreasFest is also attended by representatives from industry and patient-focused foundations, such as CAPER, Mission:Cure, Rebecca’s Wish and the National Pancreas Foundation. The R13 funding is intended to support registration and travel for faculty, specifically for new investigators and trainees. PancreasFest 2026 will be held at the Graduate Hotel on the University of Minnesota campus in Minneapolis from July 22-24, 2026.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Because it is unsafe to access human pancreatic islets from living donors, surrogate experimental systems are needed to answer important questions about the mechanisms through which insulin-producing β cells are destroyed in individuals who develop type 1 diabetes (T1D). Protocols for differentiating induced pluripotent stem cells (iPSCs) into islet-like clusters (SC-islets) provide a replenishable source of beta cells and are a promising alternative means for modelling interactions between human islet endocrine cells and immune cells. However, currently available biomimetic systems are not able to maintain the long-term viability of SC-islets and are not isogenic and therefore, unable to accurately model autoimmune interactions. To meet this need, this project will develop a vascularized 3D biomimetic microphysiological system (MPS) that will allow fully isogenic modelling of interactions between islets and immune cells in prolonged culture. Our basis for this model system is a proven perfusion-capable microfluidic skin-on-chip platform. This plexiglass-based chamber system has an open well on the top, which is readily adaptable to create an ideal system for culturing SC-islets. A microchannel network within the chamber promotes the formation of a vascular network in a supporting matrix. The system has been designed with inlet and outlet ports for perfusing endothelial cells, medium, cytokines, or immune cells. Furthermore, the system is configured to allow live imaging and removal of SC-islets and immune cells from the system for downstream analysis. We predict that this approach will overcome some of the described limitations of existing SC-islet culture systems and will allow mechanistic interrogation of mechanisms that promote sustained autoimmunity and pathologic interactions between SC-islets and autoreactive T cells. We will fully implement this system and demonstrate its suitability for studying interactions between human SC-islets and autoreactive T lymphocytes and then utilize it to ask specific questions about the effects of inflammatory stress on SC-islet phenotype. Importantly, our experiments will utilize T cell lines and T cell receptor sequences obtained from pancreatic organ donors with T1D, as these represent the most relevant T cells for mechanistic studies. Specifically, we will investigate the effects of inflammatory stress on islet phenotype, function and interactions with autoreactive T cells, first using 3D cultures (suitable for modeling short-term inflammatory stress) and then in the islet-on-chip system (suitable for short and long-term inflammatory stress). This will enable us to test the hypothesis that inflammatory stress alters beta cell phenotype and drives increased immune perception during the development of T1D. In addition, we will utilize the islet-on-chip system to investigate the role that the membrane repair pathway plays in dictating the vulnerability of beta cells to immune attack. We anticipate that modeling interactions between SC-islets and cytotoxic T cells will reveal a crucial role of the membrane repair pathway in determining vulnerability to immune attack. These insights are likely to suggest novel pathways that can be leveraged to treat T1D.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Project Summary/Abstract Fetal lower urinary tract obstruction (LUTO) is a rare but life-threatening congenital condition that causes progressive renal damage, pulmonary hypoplasia, and high perinatal mortality. Vesicoamniotic shunting (VAS) offers a means of restoring bladder drainage and preserving fetal organ development, but current shunting devices are highly unreliable. Existing options are associated with dislodgement and mechanical malfunction in over 50% of cases, often necessitating repeat procedures that increase fetal and maternal risk. The Q-shunt is a novel, anatomically stable fetal shunting device designed to overcome the limitations of current technology. Its patented design includes a self-expanding nitinol anchor to prevent dislodgement and a bidirectional delivery system that allows for real-time placement adjustment—two innovations that address the root causes of VAS failure. Preliminary clinical experience with a proof-of-concept prototype demonstrated 93% proper placement, 100% device retention, 88% live birth rate, and 72% of cases had normal renal function at 2 years of age. Phase I SBIR funding will facilitate device refinement while maintaining the anchoring strength and maneuverability of the Q-shunt. This project will establish the feasibility of an optimized Q-shunt design through materials refinement, functional performance validation, and risk mitigation in preparation for clinical trials. The work will include: (1) selection and testing of biocompatible materials for optimal clinical performance; (2) performance validation through bench testing of flow rate, yield point, tensile strength, curl strength, and anchoring retention; (3) development of engineering specifications and regulatory-compliant design drawings; and (4) prototype assembly and final bench testing for compliance with predefined safety, usability, and performance benchmarks. A medical device manufacturing firm will be subcontracted for device miniaturization and mechanical optimization. The finalized prototype will be suitable for regulatory engagement and serve as the basis for a Phase II clinical safety trial. A validated Q-shunt prototype offers a safe, reliable, single-procedure solution for fetuses with LUTO, minimizing fetal and maternal risk and reducing overall healthcare costs. Projected revenues are $6.5M within five years based on 50% penetration among specialized antenatal care centers, targeting a ~$13M annual U.S. market. With bench-tested performance data and finalized engineering plans, the project will be positioned for Phase II SBIR funding, preclinical regulatory discussions, and strategic investor engagement.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT CMTx Biotech is an emerging drug development company working to commercialize novel, host-directed, small molecule drug candidates invented at partnering academic research institutions for the treatment of diseases with high unmet medical needs, including orphan indications and conditions for which there are limited treatment options. Hemorrhagic cystitis (HC) is a severe inflammatory condition of the lower urinary tract (LUT) that leads to hematuria, blood clots in urine, dysuria, fever, inability to urinate, and loss of bladder control. HC is most common in patients treated with ifosfamide and high-dose cyclophosphamide (CYP) in the setting of bone and soft tissue sarcoma and hematopoietic cell transplantation, or as a late toxicity of pelvic radiation therapy (RT) when the bladder is within the radiation treatment field. HC occurs in up to 70% of patients exposed to high doses of CYP or ifosfamide chemotherapy, and in 5-10% of patients who undergo pelvic irradiation to treat malignancy. Current management strategies and therapies include supportive measures, intravesical astringents or the drug sodium 2-mercaptoethane sulfonate (mesna). Mesna is associated with a number of adverse effects. Importantly, findings from a number of studies including a retrospective study of 718 patients receiving CYP with or without mesna do not support the use of mesna as a preventative measure against HC in patients receiving CYP and suggest that mesna may actually be harmful in such patients. Thus, there remains a critical unmet need for safe and effective therapeutics for the treatment of HC. The product of this STTR will be a novel, orally administered small molecule, 8-aminoguanine (8-AG), for the treatment of patients with HC. We anticipate the 8-AG will be a safe and effective treatment for HC patients by reducing bladder inflammation and bleeding, promoting healing of the bladder lining, and relieving symptoms including bladder pain, as well as urinary frequency, urgency and dysuria. The Specific Aims of this STTR are (a) to conduct oral 8-AG dose optimization to identify a dose that preserves efficacy (e.g., improve LUT function, reduce nocifensive behavior) in a rat model of CYP induced HC and (b) to determine the potential genotoxicity of 8-AG by the bacterial reverse mutation test, commonly known as the Ames test. We anticipate that 8-AG will significantly improve LUT structure and function in a rat model of CYP-induced HC. Our long-term goal is to secure FDA approval for 8-AG as a safe and effective treatment of HC patients. Successful completion of these studies will allow CMTx Biotech to (a) prepare and submit a pre-IND meeting request and briefing document, (b) scale-up cGMP production of 8-AG, (c) develop and manufacture an orally-administered formulation of 8-AG, (d) conduct IND-enabling, non-clinical toxicology studies, (e) design a Phase I clinical trial, and (f) submit an Investigational New Drug (IND) application focused on this indication. As technical and regulatory milestones are achieved, we will work to forge a strategic partnership with an established pharmaceutical company in the form of a license, co-development agreement, or acquisition.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Myelodysplastic Syndromes (MDS) is a group of heterogenous bone marrow failure syndromes often seen with advancing age. Mutations in splicing factors (SFs) such as SF3B1, U2AF1 and SRSF2 are the driving genetic alterations in over half of all MDS. These mutations have classically been linked to alternative splicing of oncogenes or tumor suppressors, but recent studies suggest broader defects including disruption of co-transcriptional splicing, which is the close functional coupling of transcription and splicing. Our group has recently shown that mutant SF3B1 impairs spliceosome assembly and slows RNA Polymerase II (Pol II) elongation, resulting in transcription-replication conflicts and replication stress. These changes reorganize chromatin, reducing promoter accessibility and histone marks. Notably, this model can explain the mutual exclusivity of SF mutations: cumulative transcriptional stress from multiple mutations is unsustainable for clonal expansion. In this application, we seek to define the role of HTATSF1, a protein with roles in both splicing and transcription, in transcriptional dysregulation in SF-mutant MDS. Our preliminary results show reduced interaction of HTATSF1 with mutant SF3B1. We hypothesize that this reduced binding of HTATSF1 to mutant SF3B1 impairs its recruitment to Pol II, disrupting the coordination between transcription and splicing. Conventional genome-wide assays lack spatial and temporal resolution to study the complexity of highly dynamic complexes such as spliceosome and Pol II. To overcome this, we will use multi-color, single-molecule imaging to resolve HTATSF1 recruitment and interaction kinetics in real time. We have leveraged CRISPR/Cas9 to introduce tags (degron for acute degradation and HaloTag for high resolution live-cell imaging in primary murine embryonic stem cells. Two aims are proposed to determine HTATSF1’s role in SF-mutant MDS. In the first aim, we will study how impairment of transcription noted in SF-mutant MDS is linked to HTATSF1. Total Internal Reflection Fluorescence (TIRF) microscopy will be used to track endogenously tagged HTATSF1 at a single-molecule resolution. In the second aim, we will determine HTATSF1’s role in altered splicing, a feature of SF-mutant We will utilize single-molecule imaging as well as differential phosphoproteomics in these studies. Ultimately, our findings may inform the development of therapies targeting transcriptional dysregulation, replication stress, and chromatin dysregulation in MDS.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY: 2026 Control of Renal Function in Health and Disease: Next Generation This NIH R13 grant application seeks support for a travel award program for the upcoming 2026 conference entitled “Control of Renal Function in Health and Disease: Next Generation”. The American Physiological Society is sponsoring this conference, which is scheduled for June 22-26, 2026 in Fontana-on-Geneva Lake, Wisconsin. There are several major translational and therapeutic areas included in the meeting that have relevance to the scientific community. To encourage engagement and participation of trainees and early career investigators in the field, we propose implementing an NIH-funded travel award program specifically designed to support their attendance at the conference. Nearly half of U.S adults have hypertension, and among those affected, only 24% have their blood pressure under control. Both clinical and preclinical studies have demonstrated that hypertension alters the kidney's ability to maintain salt and water homeostasis through disruptions in renal hemodynamics and inflammation-driven mechanisms. Thus, the kidney is central to the pathogenesis of hypertension and is a major target of end-organ-damage, which further exacerbates hypertension. Furthermore, the rising prevalence of obesity, metabolic syndrome and diabetes has significantly contributed to the increasing incidence of chronic kidney disease (CKD). Also, the incidence of acute kidney injury (AKI) is increasing, driven by a rise in ischemic and nephrotoxic events. As such, it is essential to deepen our understanding of how hypertension, CKD, and AKI contribute to the development of kidney injury. Over the past 5 years, several novel methodologies have emerged for studying kidney function and disease, offering valuable insights for both renal physiologists and nephrologists alike. Therefore, there is a strong need within the scientific community for a dedicated conference addressing these critical topics. The organizing committee has designed a meeting program that highlights emerging areas in kidney function and disease including symposia on topics such as obesity, diabetes and metabolic syndrome; inflammation and the kidney; developmental programming of kidney disease; genetics, epigenetics of the kidney; immunology and the kidney, circadian biology of kidney function, single cell RNAseq and spatial transcriptomics in kidney disease and organoids. The symposia will also explore recent advances in established areas of renal research including hemodynamics, acute kidney injury, integrative control of kidney function, chronic kidney disease, autocoids and the impact of nutrition on kidney function and hypertension.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY/ABSTRACT Reprogramming is crucial for cellular renewal in adult organs that lack dedicated stem cells to replace loss after injury and inflammation. Because such cell plasticity is likely to be executed by a conserved cellular program, we have begun to identify the conserved cellular-molecular features of the process of recruiting differentiated cells as progenitors. The term paligenosis has been recently coined to describe an evolutionary conserved process that a differentiated cell uses to downscale its organelle contents, activate a progenitor-like gene network, and reenter the cell cycle. The upstream triggers and molecular mechanisms initiating this regenerative program remain poorly understood. This project investigates upstream triggers of paligenosis. Using a high-dose tamoxifen injury model to induce paligenosis in zymogenic chief cells of murine stomach corpus, ultrastructural changes in the rough endoplasmic reticulum (rER) were observed during paligenosis initiation (e.g., swelling of the rER lamellae, liberation of ribosomes from rER, and overall loss of ER). This leads to the hypothesis that dynamic changes in ER are an upstream event in paligenosis. ER functioning is in part monitored by the integrated stress response with the paramount ER stress sensor being PERK, a kinase that inhibits translation of mRNA on the ribosome by phosphorylating the translation initiation protein elF2a. Phosphorylated elF2a halts global translation while upregulating a specific set of genes to restore homeostasis. Data show that high-dose tamoxifen activates the integrated stress response in paligenotic zymogenic chief cells, triggering global attenuation of protein synthesis. Preliminary data also indicate that disassembly of rER is an early paligenosis event, supporting the hypothesis that early events of paligenosis are driven by the PERK-integrated stress response pathway and the dynamic regulation and autophagy of rER. Aim 1 of this project thus seeks to detail activation of PERK over a lime course early in paligenosis in the high-dose tamoxifen injury model, and then test the PERK requirement using PERK and integrated stress response inhibitors, and Pefkllll mice crossed to chief cell-specific promoter mice. Sufficiency will be tested by inducing ER stress and by drug-induced activation of PERK. Aim 2 will detail paligenotic ER remodeling in a high-dose tamoxifen model. Using ER-phagy defective mice (Ccpgt+), the effect of ER-phagy deficiency on paligenosis will be examined. The necessity of ER-phagy receptor in initiating and regulating autophagy will also be examined in a clinically relevant context, using human gastric adenocarcinoma cell line AGS and patient-derived organoid models of normal gastric corpus and intestinal metaplasia. This fellowship project ultimately seeks to define critical upstream events that initiate cellular reprogramming during regeneration, providing new insights into ER stress signaling and ER-phagy in gastrointestinal tissue repair and disease. This fellowship also supports a mentored training plan focused on the development of skills related to project management, imaging and analytical techniques, teaching, communication, leadership, and outreach.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

Abstract Support is requested for a Keystone Symposia conference entitled Reimagining Diabetes: From Molecular Mechanisms to Transformative Therapies, organized by Drs. Anna Krook, Jennifer Green and David Moller, with scientific programming input from Keystone Symposia. The meeting will take place January 31–February 04, 2027, at Keystone Resort in Keystone, Colorado. Despite breakthrough medicines, the burden of diabetes and comorbid conditions – including obesity, cardio- renal disease and others – continues to rise at an alarming rate. This meeting on Reimagining Diabetes: From Molecular Mechanisms to Transformative Therapies, planned in collaboration with the Endocrine Society, will explore gaps and challenges in our understanding of pathobiology of diabetes and define emerging therapeutic approaches that hold promises for addressing unmet clinical needs and reversing the trajectory of disease progression. The primary goals of the Keystone Symposia–Endocrine Society conference series are to integrate ‘bench-to-bedside-and-back’ perspectives and to increase crosstalk among basic, translational and clinical researchers across endocrine and metabolic-related areas, with the intent of spurring innovative basic research informed by real-time clinical insights that will, in turn, create new therapeutic hypotheses, accelerate future clinical development and enhance treatment outcomes across disease areas. This specific conference aims to share knowledge, spark scientific collaboration, and generate new research and development ideas. It will focus on three themes: (1) basic science, including genetic research into disease causation; (2) novel therapeutic targets and strategies, emphasizing non-incretin and disease-modifying approaches; and (3) innovative research and clinical tools for enhancing therapeutic impact. The meeting will bring together established and early-career researchers from diverse fields who infrequently collaborate, creating a unique platform for interaction among academic researchers, industry scientists, and clinical investigators. Beyond the scientific talks, the conference will include interactive workshops and panels focusing on lessons from clinical trials, broader discussion of improving health outcomes and an emphasis on career development of early-career scientists.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY Hematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow (BM) that comprise multiple cellular constituents, including nerves, with vital regulatory functions. Our previous studies established that the nociceptive nervous system is an essential BM niche component controlling HSC mobilization from the bone marrow into the peripheral blood. Our new preliminary resutls reveal that aging is associated with a progressive loss of nociceptive innvervation in the bone marrow, and that supplementaiton of nociceptive nerve-derived CGRP attenuates the expansion and BM HSCs in aged mice, restores their engraftment ability, and reverses the myeloid-biased differentiation. Based on these findings, we hypothesize that nociceptive nerve-derived CGRP is a critical rejuvenating signal for aged HSCs, and that targeted chemogenetic activation of BM nociceptive neurons using DREADDs can be harnessed to reverse HSC aging in vivo. In the Specific Aim 1, we will determine whether CGRP administration reverses bona fide aging hallmarks and identify the downstream molecular programs that mediate this rejuvenation. In Specific Aim 2, we will investigate whether local activation of BM nociceptive neurons using DREADDs rejuvaentes old HSC in vivo. Together, these proposed studies will shed light into the critical functions of an under-appreciated component of the HSC niche and uncover novel therapeutic strategies for age-associated hematopoietic diseases.

NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases

PROJECT SUMMARY The vagus nerves transmit sensory information from the gastrointestinal tract to the brain, playing a crucial role in the neural control of feeding and energy homeostasis. These signals are conveyed to brain systems that regulate both the homeostatic control of feeding and the cognitive aspects of food reward. The gut-innervating afferent fibers of the vagus nerve demonstrate lateralized activation of midbrain “reward” circuitry, with projections through the right, but not the left, vagus nerve driving reward-related behaviors and dopamine release. One key hormone involved in feeding regulation is cholecystokinin (CCK), a peptide released in the gut in response to food intake. Acting through the vagus nerve, CCK signaling is traditionally known to promote satiety, a physiological state in which feelings of fullness signal the cessation of eating. However, recent research has shown that CCK also plays a critical role in the vagal signaling pathways that drive post-ingestive macronutrient preference. The ability of vagal CCK signaling to reinforce food-seeking behaviors suggests that it may play a role in vagally-mediated reinforcement. The central hypothesis of this proposal is that asymmetrically expressed CCK receptor-expressing vagal neurons critically contribute to lateralized interoceptive reward signaling. The goal of this project is to determine the extent to which these neurons contribute to lateralized vagus-mediated reinforcement of appetitive behaviors. In Aim 1, we test the hypothesis that right vagal neurons are more responsive to CCK than left vagal neurons. In Aim 2, we test the necessity of right versus left CCK receptor-expressing vagus neurons in the development of fat preference. In Aim 3, we determine the extent to which CCK receptor-expressing vagal neurons are required for the reinforcement of learned behaviors by right vagus nerve stimulation (VNS). These experiments will reveal new insights into the mechanisms underlying lateralized interoceptive reward signaling. In doing so, the proposed work will critically inform the development and optimization of VNS and other therapeutic approaches for the treatment of obesity and metabolic disorders.