2019 — 2020 |
Evans-Molina, Carmella Ferrannini, Eleuterio |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Modeling Islet Dysfunction During Type 1 Diabetes Progression @ Indiana Univ-Purdue Univ At Indianapolis
PROJECT SUMMARY/ABSTRACT Over the past 30 years, a number of immunomodulatory agents have been tested in type 1 diabetes (T1D). While a handful of these trials met their primary endpoint, defined as an improvement in the C-peptide area under the curve response during a mixed meal tolerance test, no immunomodulatory intervention has yet proven capable of inducing insulin independence. Furthermore, no drug has been approved as a disease-modifying therapy for T1D, highlighting an important gap in translating T1D trial results into clinical practice. Here, we will test the hypothesis that targeted and model-based approaches to document early changes in ? cell function can refine current strategies aimed at preventing loss of insulin secretion in T1D. We have previously developed and validated a robust mathematical method to model dynamic parameters of ? cell function ? including ? cell glucose sensitivity, rate sensitivity, and potentiation ? and to estimate insulin sensitivity from standard oral glucose or mixed meal tolerance tests, known as the Mari/Ferrannini model. Here, we will apply the Mari/Ferrannini model to existing datasets from completed T1D intervention studies, performed in the Type 1 Diabetes TrialNet and the Immune Tolerance Networks, to define the natural history of ? cell decline in placebo-treated subjects (Aim 1) and determine whether short-term changes in sensitive model-derived parameters of insulin secretion and insulin clearance can be used to identify clinical and immunological Responders and Nonresponders at study end (Aim 2). The successful completion of this work will provide a framework for the design and execution of shorter trials, help dissect disease and trial heterogeneity, and provide rationale for targeting interventions to those with the highest prospect of benefit.
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0.924 |
2020 — 2021 |
Evans-Molina, Carmella |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Administrative Core @ Indiana Univ-Purdue Univ At Indianapolis
ABSTRACT (ADMINISTRATIVE CORE) The Administrative Core will leverage resources and provide administrative oversight to ensure smooth operation of the Indiana Diabetes Research Center (IDRC), including the Research Cores, Pilot and Feasibility Program, and Enrichment Program. The Administrative Core includes the Director of the IDRC, Dr. C. Evans- Molina, the Associate Director, Dr. K. Mather, the Executive Administrative Assistant, the Business Manager, and the Communications Specialist. To support the mission of the IDRC, the Administrative Core will leverage resources and provide administrative oversight to ensure operation of the Research Cores and the Pilot and Feasibility Program. In addition, the Administrative Core will create an environment that enriches collaboration and interaction by providing oversight of the Seminar Series and the Annual Diabetes Symposium. The Co- Directors assume responsibility for the scientific and educational directions of the Center. The Associate Director will assist the Directors as needed in the operation of the IDRC. The aims of the Administrative Core will include: (1) Encourage membership in the IDRC to ensure the continued growth of the Center's Research Base of investigators. (2) Foster the careers of new and promising investigators in the field of diabetes and metabolic disorders by providing funding, scientific expertise and guidance, and access to technical resources through the Pilot and Feasibility Program. (3) Allocate resources (including equipment, personnel, and funds) and oversee charge-back policies to ensure the financial health of each Research Core and the appropriate flow of reagents and samples between Cores. (4) Create an environment that meets the needs of the Research Base and facilitates success through evolution of the Research Cores. (5) Minimize redundancy of Core services and charge-backs, and to maximize interaction and collaboration with investigators from other research disciplines. (6) Create a stimulating atmosphere that facilitates the training and education of faculty and learners at all levels through the operation of an Enrichment Program (7) Inform the Research Base and local community of IDRC activities including seminars, Research Core services, availability of Pilot and Feasibility funds, and local diabetes-related events through the maintenance of a dedicated website.
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0.924 |
2020 — 2021 |
Evans-Molina, Carmella |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Indiana Diabetes Research Center @ Indiana Univ-Purdue Univ At Indianapolis
ABSTRACT (OVERALL CENTER) The mission of the Indiana Diabetes Research Center (IDRC) is to foster knowledge, support training, and promote basic and translational research in diabetes and related metabolic disorders, and their complications. A major focus of the IDRC has been the training and development of the ?next generation? of diabetes researcher. This focus has involved a state-wide effort led by the IDRC that has included resource provision (through the Research Cores), financial support and mentoring (through the Pilot and Feasibility Program and institutional funds), and creation of a collaborative diabetes ecosystem (through the Enrichment Program) for a burgeoning pool of investigators at Indiana University School of Medicine and its affiliated research institutions in Indiana (Purdue University, Indiana University-Purdue University in Indianapolis, Indiana University Bloomington, and the Indiana Biosciences Research Institute). The IDRC has been the catalyst for the growth of the Diabetes Research Base by 47% since the funding of this award in 2015. The IDRC consists of a Research Base of 94 highly collaborative investigators who represent 4 research themes: Cellular & Molecular Metabolism; Complications of Diabetes & Obesity; Islet Function & Survival; Nutrition & Physiology of Diabetes and Obesity. Collectively, this group of investigators brings in $46.7M in annual directs from the NIH, of which 50% ($23M) is from NIDDK. The research programs of these investigators is be augmented by 5 state-of-the- art Research Cores (Microscopy, Islet & Physiology, Translation, Swine, and Systems & Informatics Cores). An Enrichment Program, supported by 6 T32 training grants, will enhance learning and discovery. A Pilot and Feasibility Program will grow the Research Base by providing funding to highly promising young investigators. An Administrative Core will oversee governance of the IDRC, and will receive input from an Executive Committee, an Internal Advisory Board, and an External Advisory Board of world-renowned diabetes/metabolism research leaders. The Aims of the IDRC will be to: (1) Promote high impact scientific discoveries by leveraging Research Cores that facilitate collaborations and the use of state-of-the-art methodologies and human studies in diabetes research; (2) Enhance a highly collaborative environment that promotes learning and encourages interaction among investigators; (3) Support the training and innovative research of a burgeoning pool of superb investigators with the potential to become future leaders in diabetes research; (4) Build and strengthen the diabetes research base, support infrastructure to ensure ongoing growth and innovation, and engage with the local community to raise diabetes awareness and involvement.
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0.924 |
2020 — 2021 |
Evans-Molina, Carmella Voytik-Harbin, Sherry L [⬀] |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Interdisciplinary Bioengineering Training in Diabetes Research
PROJECT ABSTRACT Diabetes is a debilitating and burdensome public health problem, affecting an estimated 29.1 million men, women, and children (9.3% of total population) in the U.S. alone. Patients with this and other related metabolic disorders are burdened with devastating quality of life and health consequences, making the need for proper disease management paramount. As a result, there is an urgent demand for transformative technologies that provide both physicians and patients with more options to prevent, diagnose, treat, and cure diabetes, metabolic diseases, and their complications. Furthermore, an interdisciplinary workforce is needed to accelerate development and delivery of these cutting-edge technologies to the clinic and market. The Bioengineering Interdisciplinary Training in Diabetes Research (BTDR) Program, which was initiated in 2013, was strategically designed to meet this need. A notable aspect of the program is that it integrates the strength in engineering education and technology development found at Purdue with excellence in diabetes research found at Indiana University School of Medicine, yielding an uncommon cross-fertilization. The mission of the BTDR program is to develop the next-generation interdisciplinary workforce that innovates, designs, and translates bioengineering technologies to advance the mechanistic understanding, prevention, and treatment of diabetes and its complications. The aims of the BTDR program are to: 1) recruit highly talented students in engineering, physical sciences, computational sciences, analytical chemistry, pharmacology, physiology, and endocrinology with strong research backgrounds and commitment to innovative technology development and diabetes related research; 2) ensure that the next generation of interdisciplinary educators, scientists, policy makers, and physicians includes individuals from diverse ethnic, social, economic, and regional backgrounds, maximizing the scope and breadth of societal impact; and 3) engage students in a novel training experience that integrates basic research, innovation, design, entrepreneurship, and translation, along with vertical mentoring, to develop an integrated workforce that is equipped to accelerate advanced diagnostics and therapeutics to market. The proposed training program provides training pathways for six predoctoral students (two years support per student) from various engineering, physical science, and medical science disciplines, culminating in PHD or MD-PHD degrees. BTDR offers an uncommon interdisciplinary curriculum and rigorous hands-on training focused on technology design and translation guided by faculty with expertise in the cross- cutting areas of Therapeutic Cell & Drug Delivery, Biosensing & Biomaging, Informatics & Modeling, and Molecular Mechanisms & Drug Targets. Trainee outcomes include the ability to operate beyond hypothesis- driven research, incorporating principles of engineering design, standardization and validation, regulatory policy, technology translation, and entrepreneurship.
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0.961 |
2020 — 2021 |
Evans-Molina, Carmella |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Islet & Physiology Core @ Indiana Univ-Purdue Univ At Indianapolis
ABSTRACT (ISLET & PHYSIOLOGY CORE) The Islet & Physiology Core supports the overall mission of the Indiana Diabetes Research Center (IDRC) to foster collaboration, support training, and promote cutting edge research in diabetes and related metabolic disorders by providing comprehensive and state-of-the art services in rodent islet isolation; zebrafish, rodent, swine, and human islet characterization; human, rodent, and swine islet transplantation; and rodent metabolic phenotyping. The Islet and Physiology Core supports the work of IDRC investigators from Indiana University School of Medicine (IUSM) and its affiliated institutions, working closely with members to provide ?wrap- around? services that include assistance with experimental design, efficient execution of experiments, and assistance with data analysis and interpretation. The Core serves both experienced as well as novice users and functions as an important conduit for facilitating entry into the field for investigators who have not traditionally worked with islets or performed metabolic research. In addition to consultative and experimental services, the Core provides training for investigators who wish to incorporate specialized techniques back into their own lab. The Director of the Core is Dr. C. Evans-Molina, the Associate Director is Dr. S. Tersey, and the Assistant Director is Dr. R. Anderson. The leadership is assisted by a crew of technical staff and advised by an Advisory Board. The Core closely interfaces with the IDRC Translation Core, Microscopy Core, Systems & Informatics Core, and Swine Core to meet the experimental needs of our user base, while also adhering to the highest standards of rigor, reproducibility, refinement, and reduction. The Core will achieve the following aims: (1) To provide IDRC investigators with high quality rodent islets and facilitate the procurement of human and swine islets and pancreatic tissues for analysis. (2) To provide state-of-the-art human, rodent, zebrafish and swine islet and pancreas characterization services. (3) To provide state-of-the art rodent metabolic analysis, including assessment of glucose and insulin tolerance, body composition, energy expenditure, activity levels, and food intake. (4) To provide consultation services and training that is tailored to fit the needs of both experienced users and users who are new diabetes and metabolic research. (5). To ensure that Core services evolve to meet IDRC investigator needs and keep pace with new developments in the field
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0.924 |
2021 |
Evans-Molina, Carmella |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
? Cell Mirnas Function as Molecular Hubs of Type 1 Diabetes Pathogenesis @ Indiana Univ-Purdue Univ At Indianapolis
Type 1 diabetes (T1D) is a chronic metabolic disorder that is characterized by immune-mediated ? cell destruction, resulting in the lifelong need for exogenous insulin therapy. Historically, T1D has been considered a disease of ? cell homicide. However, recent evidence suggests that the ? cell actively contributes to its own demise in T1D through engagement of cell intrinsic stress pathways that both hasten cell death and exacerbate autoimmunity. microRNAs (miRNAs, 18-25 nt) are a class of small non-coding RNAs that post transcriptionally modulate gene expression by binding the 3?untranslated region of a target mRNA to either inhibit mRNA translation or cause mRNA degradation. In addition to these regulatory roles within their cells of origin, miRNAs can be packaged and released within extracellular vesicles (EVs), which can be transferred to recipient cells to both facilitate intercellular communication and promote disease pathogenesis. While miRNAs have been shown to regulate several key processes within the ? cell and have been implicated as potential mediators of a dialogue between the immune system and the ? cell in diabetes, a full understanding of the role of miRNAs in T1D pathophysiology remains elusive. To this end, we profiled changes in miRNA expression patterns in human islets and islet-derived extracellular vesicles (EV?s) in response to IL-1? and IFN-?, two cytokines selected to model the inflammatory intra-islet milieu observed in T1D. Our initial small RNA sequencing and additional preliminary data has shown that islet miRNA expression patterns are responsive to inflammatory extrinsic cues and that miRNAs appear to be selectively packaged into islet-derived EV?s in response to cytokine treatment. Moreover, islet and islet-derived EV miRNAs exhibited striking sexually dimorphic expression patterns under basal conditions and following cytokine treatment. Interestingly, miR-155-5p and miR-146-5p were the only two miRNAs that were coordinately upregulated in cytokine-treated islets and islet-derived EVs from both male and female donors, and upregulation of these miRNAs was associated with detrimental changes in ? cell function and survival. Based on these findings, we hypothesize that ? cell miR-155-5p and miR-146-5p function as key molecular hubs during the evolution of T1D, playing a role in disease pathogenesis, while also having potential utility as diabetes biomarkers. To test this hypothesis, we aim to: 1) define how miRNA signatures change in human ? cells during T1D progression using state-of-the art smFISH imaging approaches, focused on miR-155 and 146 and a panel of additional miRNAs predicted to have either common or distinct expression patterns in males and females; 2) elucidate the mechanisms underlying miR-155-5p and miR-146-5p upregulation under inflammatory conditions; 3) define how miR-146 and miR-155 regulate ? cell function and survival, leveraging both ex vivo human islet models and novel mouse models of ? cell specific deletion of miR-155; and 4) test the utility of EV miRNA signatures informed from islet RNA sequencing as clinical biomarkers using plasma EVs and ? cell enriched plasma EVs collected from pediatric subjects with recent onset T1D or autoantibody positivity.
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0.924 |
2021 |
Evans-Molina, Carmella Fogel, Evan |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Indiana University Clinical Center For Acute Pancreatitis and Diabetes Clinical Research Network @ Indiana Univ-Purdue Univ At Indianapolis
PROJECT SUMMARY / ABSTRACT Pancreatogenic diabetes, or type 3c diabetes (T3cDM), is a known complication of acute pancreatitis (AP). Recent data suggest that T3cDM occurs more commonly than previously recognized and exhibits a spectrum of defects including features that overlap aspects of both type 1 and type 2 diabetes. At present, the extent to which immune activation, ? cell dysfunction, and insulin resistance occur following AP and the genetic, metabolic and imaging correlates of these phenotypes have not been characterized. To address these knowledge gaps, we have assembled a multidisciplinary team with expertise in pancreatitis and exocrine pathophysiology, diabetes, ? cell biology, diabetes genetics, and pancreatic imaging at the Indiana University School of Medicine. The IU Clinical Center will work with other members of the Type 1 Diabetes in Acute Pancreatitis Consortium to test the hypothesis that T3cDM encompasses a heterogeneous combination of metabolic and potentially immunologic phenotypes that are determined by distinct underlying pathophysiologies. We propose the following specific aims (SA) to meet the goals of this RFA. SA #1: To perform an observational study of robustly characterized adults with AP in order to address knowledge gaps in the natural history and incidence of autoantibody-positive diabetes (AAb+), impaired glucose tolerance (IGT)/impaired fasting glucose (IFG), and diabetes occurring subsequent to AP. Enrolled participants will be longitudinally characterized with emphasis on identifying genetic, immunological, metabolic, and clinical risk factors for the development of AAb+, IGT/IFG, or T3cDM. We will use state-of-the-art immunologic phenotyping and measurements of pancreatic ? cell function to define the physiologic basis for metabolic dysregulation in T3cDM after AP. In tandem, a biorepository will be developed for undertaking translational, mechanistic and biomarker investigations and ancillary studies. SA#2: The Imaging Morphology of Pancreas in Diabetic Patients following Acute Pancreatitis (IMMINENT) study aims to utilize novel quantitative magnetic resonance imaging techniques as a non-invasive biomarker to identify patients at risk for the development of post-AP T3cDM. This longitudinal study will evaluate pancreatic parenchymal morphologic and pathophysiologic changes following AP in AAb+, euglycemic, IGT and DM individuals. Imaging phenotypes will be correlated with the metabolic, genetic and immunological phenotypes established in SA#1. SA#3: To perform a nested case control study using state-of-the-art techniques to define the underlying pathophysiology of endocrine and exocrine function in the subgroup of AAb+ individuals with AP-associated metabolic dysfunction relative to those who remain normoglycemic. We will undertake detailed metabolic phenotyping to evaluate islet cell responses (i.e. ? and alpha cell function) in parallel with arginine-augmented hyperglycemic clamp methodology to measure functional ? cell mass, and endoscopic assessment to define the relationship between impaired exocrine and endocrine function in AAb+ T3cDM. We will utilize 25 individuals with AAb+ and IGT or T3cDM and compare findings to results in 25 normoglycemic individuals with negative autoantibodies from SA#1.
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0.924 |
2021 |
Eizirik, Decio Laks Evans-Molina, Carmella Metz, Thomas O (co-PI) [⬀] Mirmira, Raghavendra G [⬀] Ramanadham, Sasanka Webb-Robertson, Bobbie-Jo Mary |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Integrated Stress Response in Human Islets During Early T1d
ABSTRACT The pathogenesis of type 1 diabetes (T1D) encompasses a spectrum ranging from aggressive autoimmunity toward islet ? cells to defects in ?-cell function that arise from inflammation. A perspective that has been gaining traction in recent years posits that intracellular signaling pathways arising from the ? cell response to inflammation can lead to the production of aberrant proteins that serve as neoantigens that initiate or exacerbate autoimmunity. This perspective has prompted our Team to identify and intervene in intracellular signaling pathways that affect ?-cell resilience as T1D progresses from the presymptomatic to symptomatic stages. This proposal takes a multidisciplinary Team Science approach that is responsive to RFA-DK-19-024 to define and intervene in early T1D disease processes affecting human islets. The integrated stress response (ISR) is a cytoprotective process whereby environmental stress signals are transduced intracellularly to activate a host of eIF2? kinases. The phosphorylation of eIF2? halts general mRNA translation initiation in an effort to redirect energy expenditure to mitigate the prevailing stress. The translationally inhibited mRNAs and their associated proteins are sequestered into intracellular stress granules (SGs), the formations of which are thought to divert cellular signaling toward an emergency response. Our preliminary data suggest that the ISR is activated in islets during early T1D, and that the pathway linking membrane-derived lipids to the production of proinflammatory lipid intermediates may trigger the ISR and the formation of SGs. We hypothesize that the activation of the ISR and formation of SGs is an early cellular response initiating ? cell stress in T1D that determines cell survival and can be monitored in pre- and early T1D individuals with minimal invasiveness. Our collaborative Team will test this hypothesis through the following aims: Aim 1: Define the mechanisms of stress granule formation and their fate upon activation of the integrated stress response in human islets. Aim 2: Determine the molecular events linking lipid metabolism, activation of the ISR, and stress granule formation in human islets. Aim 3: Identify protein, RNA, and lipid cargo in EVs as putative biomarkers of the human islet integrated stress response and T1D risk. This application leverages the expertise of 6 Multi-PIs in ?-cell biology, lipid and eicosanoid biology, functional genomics, proteomics, computational modeling, and clinical islet studies. The impact of this project will be to deliver new knowledge on an unstudied stress pathway in human islets and to identify and validate biomarker panels that reflect this stress state.
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0.948 |