R01DK138372

Virome and immune responses associated with IA and type 1 diabetes - the goal of this project is to integrate analysis of viral and immune responses using white blood cells, nasal swabs and plasma from 450 children previously collected from the prospective cohort TEDDY study, to build upon previous TEDDY findings that strongly implicated prolonged infections with type B enteroviruses in the development of islet autoimmunity (IA). This will further determine if prolonged enterovirus infections are linked to development of IA and type 1 diabetes (T1D), and will provide mechanistic insights into how prolonged infections may trigger disease outcomes.

Specifically, this project will combine two nested case control studies within TEDDY using stool virome analysis currently underway to find additional instances of children with prolonged infections, work being carried out by COPIS in this application. In Aim 1 we will complete the longitudinal disease risk profile of enterovirus infections for all TEDDY children developing IA or T1D by the age of 6. This will combine analysis of stool, peripheral blood mononuclear cells (PBMC) and nasal swabs using proven qRT-PCR, AmpliSeq approaches.

The findings will be used to select PBMC samples from children with confirmed prolonged infection with enterovirus in Aim 2. These will be subjected to detailed multi-‘omic single cell analysis to define cellular immune changes associated with prolonged infection and with the subsequent development of autoimmunity. Aim 3 will analyze plasma samples from a subset of children to determine whether quantitative or qualitative changes in humoral immunity to enteroviral infection may contribute to disease outcomes.

These aims together investigate, for the first time, the interaction between virus exposure, resulting cellular and humoral immune changes and subsequent risk of autoimmunity or T1D. The proposed work is significant as it will apply the power of the large, international TEDDY cohort and its prospective collection of biosamples (stool, sera and viable immune cells) to both control for potential confounders and as a source of accessory genetic and genomic data to inform to determine how prolonged infection with enterovirus is linked to islet autoimmunity.

The proposed work is innovative because it will provide the first comprehensive and integrated analysis of the virome, immune-cell intrinsic genomic responses and altered antibody responses as causal drivers of islet autoimmunity and T1D. These findings will lead to a better understanding of what triggers islet autoimmunity and T1D that will further inform hypotheses of causal mechanisms and will open conceptual avenues for key diagnostic or preventative interventions.

Baylor College Of Medicine

(1) TO PROMOTE EXTRAMURAL BASIC AND CLINICAL BIOMEDICAL RESEARCH THAT IMPROVES THE UNDERSTANDING OF THE MECHANISMS UNDERLYING DISEASE AND LEADS TO IMPROVED PREVENTIONS, DIAGNOSIS, AND TREATMENT OF DIABETES, DIGESTIVE, AND KIDNEY DISEASES. PROGRAMMATIC AREAS WITHIN THE NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES INCLUDE DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. SPECIFIC PROGRAMS AREAS OF INTEREST INCLUDE THE FOLLOWING: (A) FOR DIABETES, ENDOCRINE, AND METABOLIC DISEASES AREAS: FUNDAMENTAL AND CLINICAL STUDIES INCLUDING THE ETIOLOGY, PATHOGENESIS, PREVENTION, DIAGNOSIS, TREATMENT AND CURE OF DIABETES MELLITUS AND ITS COMPLICATIONS; NORMAL AND ABNORMAL FUNCTION OF THE PITUITARY, THYROID, PARATHYROID, ADRENAL, AND OTHER HORMONE SECRETING GLANDS; HORMONAL REGULATION OF BONE, ADIPOSE TISSUE, AND LIVER; ON FUNDAMENTAL ASPECTS OF SIGNAL TRANSDUCTION, INCLUDING THE ACTION OF HORMONES, COREGULATORS, AND CHROMATIN REMODELING PROTEINS; HORMONE BIOSYNTHESIS, SECRETION, METABOLISM, AND BINDING; AND ON HORMONAL REGULATION OF GENE EXPRESSION AND THE ROLE(S) OF SELECTIVE RECEPTOR MODULATORS AS PARTIAL AGONISTS OR ANTAGONISTS OF HORMONE ACTION; AND FUNDAMENTAL STUDIES RELEVANT TO METABOLIC DISORDERS INCLUDING MEMBRANE STRUCTURE, FUNCTION, AND TRANSPORT PHENOMENA AND ENZYME BIOSYNTHESIS; AND BASIC AND CLINICAL STUDIES ON THE ETIOLOGY, PATHOGENESIS, PREVENTION, AND TREATMENT OF INHERITED METABOLIC DISORDERS (SUCH AS CYSTIC FIBROSIS). (B) FOR DIGESTIVE DISEASE AND NUTRITION AREAS: GENETICS AND GENOMICS OF THE GI TRACT AND ITS DISEASES; GENETICS AND GENOMICS OF LIVER/PANCREAS AND DISEASES; GENETICS AND GENOMICS OF NUTRITION; GENETICS AND GENOMICS OF OBESITY; BARIATRIC SURGERY; CLINICAL NUTRITION RESEARCH; CLINICAL OBESITY RESEARCH; COMPLICATIONS OF CHRONIC LIVER DISEASE; FATTY LIVER DISEASE; GENETIC LIVER DISEASE; HIV AND LIVER; CELL INJURY, REPAIR, FIBROSIS AND INFLAMMATION IN THE LIVER; LIVER CANCER; LIVER TRANSPLANTATION; PEDIATRIC LIVER DISEASE; VIRAL HEPATITIS AND INFECTIOUS DISEASES; GASTROINTESTINAL AND NUTRITION EFFECTS OF AIDS; GASTROINTESTINAL MUCOSAL AND IMMUNOLOGY; GASTROINTESTINAL MOTILITY; BASIC NEUROGASTROENTEROLOGY; GASTROINTESTINAL DEVELOPMENT; GASTROINTESTINAL EPITHELIAL BIOLOGY; GASTROINTESTINAL INFLAMMATION; DIGESTIVE DISEASES EPIDEMIOLOGY AND DATA SYSTEMS; NUTRITIONAL EPIDEMIOLOGY AND DATA SYSTEMS; AUTOIMMUNE LIVER DISEASE; BILE, BILIRUBIN AND CHOLESTASIS; BIOENGINEERING AND BIOTECHNOLOGY RELATED TO DIGESTIVE DISEASES, LIVER, NUTRITION AND OBESITY; CELL AND MOLECULAR BIOLOGY OF THE LIVER; DEVELOPMENTAL BIOLOGY AND REGENERATION; DRUG-INDUCED LIVER DISEASE; GALLBLADDER DISEASE AND BILIARY DISEASES; EXOCRINE PANCREAS BIOLOGY AND DISEASES; GASTROINTESTINAL NEUROENDOCRINOLOGY; GASTROINTESTINAL TRANSPORT AND ABSORPTION; NUTRIENT METABOLISM; PEDIATRIC CLINICAL OBESITY; CLINICAL TRIALS IN DIGESTIVE DISEASES; LIVER CLINICAL TRIALS; OBESITY PREVENTION AND TREATMENT; AND OBESITY AND EATING DISORDERS. (C) FOR KIDNEY, UROLOGIC AND HEMATOLOGIC DISEASES AREAS: STUDIES OF THE DEVELOPMENT, PHYSIOLOGY, AND CELL BIOLOGY OF THE KIDNEY; PATHOPHYSIOLOGY OF THE KIDNEY; GENETICS OF KIDNEY DISORDERS; IMMUNE MECHANISMS OF KIDNEY DISEASE; KIDNEY DISEASE AS A COMPLICATION OF DIABETES; EFFECTS OF DRUGS, NEPHROTOXINS AND ENVIRONMENTAL TOXINS ON THE KIDNEY; MECHANISMS OF KIDNEY INJURY REPAIR; IMPROVED DIAGNOSIS, PREVENTION AND TREATMENT OF CHRONIC KIDNEY DISEASE AND END-STAGE RENAL DISEASE; IMPROVED APPROACHES TO MAINTENANCE DIALYSIS THERAPIES; BASIC STUDIES OF LOWER URINARY TRACT CELL BIOLOGY, DEVELOPMENT, PHYSIOLOGY, AND PATHOPHYSIOLOGY; CLINICAL STUDIES OF BLADDER DYSFUNCTION, INCONTINENCE, PYELONEPHRITIS, INTERSTITIAL CYSTITIS, BENIGN PROSTATIC HYPERPLASIA, UROLITHIASIS, AND VESICOURETERAL REFLUX; DEVELOPMENT OF NOVEL DIAGNOSTIC TOOLS AND IMPROVED THERAPIES, INCLUDING TISSUE ENGINEERING STRATEGIES, FOR UROLOGIC DISORDERS;RESEARCH ON HEMATOPOIETIC CELL DIFFERENTIATION; METABOLISM OF IRON OVERLOAD AND DEFICIENCY; STRUCTURE, BIOSYNTHESIS AND GENETIC REGULATION OF HEMOGLOBIN; AS WELL AS RESEARCH ON THE ETIOLOGY, PATHOGENESIS, AND THERAPEUTIC MODALITIES FOR THE ANEMIA OF INFLAMMATION AND CHRONIC DISEASES.(2) TO ENCOURAGE BASIC AND CLINICAL RESEARCH TRAINING AND CAREER DEVELOPMENT OF SCIENTISTS DURING THE EARLY STAGES OF THEIR CAREERS. THE RUTH L. KIRSCHSTEIN NATIONAL RESEARCH SERVICE AWARD (NRSA) FUNDS BASIC AND CLINICAL RESEARCH TRAINING, SUPPORT FOR CAREER DEVELOPMENT, AND THE TRANSITION FROM POSTDOCTORAL BIOMEDICAL RESEARCH TRAINING TO INDEPENDENT RESEARCH RELATED TO DIABETES, DIGESTIVE, ENDOCRINE, HEMATOLOGIC, LIVER, METABOLIC, NEPHROLOGIC, NUTRITION, OBESITY, AND UROLOGIC DISEASES. (3) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM. THE SBIR PROGRAM AIMS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO ENHANCE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. (4) TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM. THE STTR PROGRAM INTENDS TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

Houston, Texas 770303411 United States

Single Zip Code

Collaborative Research Using Biosamples from Type 1 Diabetes Clinical Studies (R01 - Clinical Trial Not Allowed) (RFA-DK-22-021)

Amendment Since initial award the total obligations have increased 194% from $1,195,882 to $3,521,569.