Natural History and Mechanisms of Exocrine Pancreatic Dysfunction in Pre-Type 1 Diabetes

1 型糖尿病前期外分泌胰腺功能障碍的自然史和机制

基本信息

批准号：
10591260
负责人：
Brittany Bruggeman
金额：
$ 15.77万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591260
关键词：
Affect Amylases Atrophic Autoantibodies Autoimmune Autoimmune Diseases Autoimmunity Autologous Beta Cell Biological Markers Birth Blood Cells Childhood Clinical Clinical Investigator Clinical Markers Clinical Research Cohort Studies Collaborations Data Deposition Development Development Plans Diabetes Mellitus Diagnosis Digestion Disease Early identification Elastases Endocrine Endocrinologist Enrollment Environment Evaluation Event Exocrine pancreas Exocrine pancreatic insufficiency Feces First Degree Relative Florida Functional disorder Funding Gene Expression Goals Heterogeneity Human Subject Research Immune Immunoglobulin G Individual Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Intervention Intervention Trial Knowledge Lead Learning Lipase Magnetic Resonance Imaging Measures Mentors Mentorship Mission Natural History Onset of illness Organ Donor Organ Size Pancreas Pathogenesis Patients Persons Phenotype Play Population Prevention strategy Prevention trial Research Research Design Research Personnel Research Proposals Research Technics Risk Risk Marker Role Sampling Scientist Serum Slice Techniques Tissues Training Translational Research Trypsinogen Universities Work biomarker evaluation career career development cohort density design diabetes pathogenesis diabetes risk early detection biomarkers experience functional loss high risk immune cell infiltrate insulin dependent diabetes mellitus onset insulin secretion islet islet autoimmunity islet cell antibody loss of function next generation novel patient oriented pre-clinical predictive marker prognostic value prospective protein expression research clinical testing skills success treatment response trial design

项目摘要

PROJECT SUMMARY. Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease. However, reduced pancreatic size and subclinical exocrine insufficiency are also present at T1D diagnosis. The mechanisms, natural history, and role of these findings in T1D pathogenesis remains unclear. Exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in some subjects, signifying that clinical measures of exocrine mass and function could be helpful early T1D biomarkers. The primary objective of this proposal is to establish the natural history of exocrine loss in pre-T1D and to identify exocrine T1D- predictive biomarkers. We will measure fecal elastase (FE-1), a clinical marker of exocrine function, throughout the course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked samples (Aim 1A). An enrolling R01-funded study of TrialNet (TN) subjects (Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI in single islet autoantibody positive (AAb+), multiple AAb+, and AAb- T1D first degree relatives (FDRs) to evaluate its prognostic utility. Herein we propose to add evaluation of serum and stool exocrine functional markers in this complementary population to evaluate their prognostic utility and determine timing of exocrine loss (Aim 1B). We hypothesize that exocrine markers will be reduced prior to Stage 1 T1D in those destined for progression and that their rate of decline can be used to predict disease onset. Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain unclear; leading hypotheses include a lack of insulin secretion or autoimmunity to exocrine tissue leading to pancreas atrophy. The secondary objective of this study will use samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) cohort to investigate these potential mechanisms and evaluate exocrine pancreatic autoantibodies as biomarkers of risk (Aim 2). We hypothesize that exocrine autoimmunity is present in subjects with multiple islet AAb+ and those with clinical T1D and leads to diminished exocrine mass and function. We hypothesize that insulinopenia is present in those with clinical T1D and leads to further exocrine atrophy. If our hypothesis is proven, this will represent a paradigm shift in our traditional understanding of the pathogenesis of T1D as an endocrine-specific autoimmune disease. This proposal will advance my early career goal to better understanding the timing and role of T1D exocrine pancreas changes and apply this knowledge in prevention and intervention trials. The skills set forth within this research proposal and career development plan will promote independence as a clinical investigator and include collaborations in several large T1D research consortia and training in 1) human subjects research trial design, implementation, and analysis 2) biomarker evaluation and 3) translational science design and technique. The collaborative rapport, excellent mentorship, and mission of training the next generation of investigators across University of Florida institutes and departments provides an ideal environment for career success.

项目摘要。 1 型糖尿病 (T1D) 历来被描述为一种内分泌（β 细胞）特异性自身免疫性疾病。 T1D 诊断中还存在胰腺体积缩小和亚临床外分泌功能不全。这些发现在 T1D 发病机制中的机制、自然史和作用仍不清楚。在某些受试者中，甚至可能先于多种胰岛自身抗体的出现（第一阶段 T1D），这表明外分泌质量和功能的临床测量可能有助于早期 T1D 生物标志物的主要目标。该提案的目的是确定 T1D 前期外分泌丧失的自然史，并识别 T1D 外分泌我们将全程测量粪便弹性蛋白酶 (FE-1)，这是一种外分泌功能的临床标志物。 TEDDY（青少年糖尿病的环境决定因素）科目中 T1D 前期的课程样本（目标 1A）。一项由 R01 资助的 TrialNet (TN) 受试者研究（Campbell-Thompson 和 Haller， mPI）将通过 MRI 前瞻性检查单个胰岛自身抗体阳性 (AAb+)、多个胰岛自身抗体阳性的胰腺体积 AAb+ 和 AAb- T1D 一级亲属 (FDR) 来评估其预后效用。评估该互补人群的血清和粪便外分泌功能标记物，以评估其预后效用并确定外分泌丧失的时间（目标 1B）。那些注定要进展的人在第一阶段 T1D 之前减少，并且他们的下降率可用于最后，预测 T1D 中胰腺外分泌质量和功能减少的机制。仍不清楚；主要假设包括胰岛素分泌不足或外分泌组织自身免疫导致这项研究的次要目标将使用来自胰腺网络的样本。患有糖尿病的器官捐献者 (nPOD) 队列研究这些潜在机制并评估外分泌胰腺自身抗体作为风险生物标志物（目标 2）。在患有多个胰岛 AAb+ 的受试者和患有临床 T1D 的受试者中，会导致外分泌质量减少，我们发现临床 T1D 患者存在胰岛素减少，并导致进一步的外分泌。如果我们的假设得到证实，这将代表我们传统理解的范式转变。 T1D 作为一种内分泌特异性自身免疫性疾病的发病机制，这一提议将推动我的早期职业生涯。目标是更好地了解 T1D 外分泌胰腺变化的时间和作用，并将这些知识应用于本研究提案和职业发展计划中规定的技能。将促进作为临床研究者的独立性，并包括在几项大型 T1D 研究中的合作 1) 人体研究试验设计、实施和分析 2) 生物标志物方面的联盟和培训评估和3）转化科学设计和技术。以及培训佛罗里达大学各研究所和下一代研究人员的使命部门为职业成功提供了理想的环境。