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

• 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
• 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

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）在历史上被描述为内分泌（β细胞）特异性自身免疫性疾病。然而，在这方面， 在T1D诊断中还存在胰腺尺寸减小和亚临床外分泌功能不全。的 这些发现在T1D发病机制中的作用、自然史和机制尚不清楚。外分泌萎缩 在某些受试者中，甚至可能先于多种胰岛自身抗体（1期T1D）的发作，这表明 外分泌质量和功能的临床测量可能是有帮助的早期T1D生物标志物。主要目的 这项建议的目的是建立前T1D的外分泌损失的自然史，并确定T1D的外分泌- 预测性生物标志物。我们将测量粪便弹性蛋白酶（FE-1），一种外分泌功能的临床标志物， TEDDY（年轻人糖尿病的环境决定因素）受试者库中的T1D前病程 样品（目标1A）。一项由R01资助的TrialNet（TN）受试者的招募研究（Campbell-Thompson和Haller， mPIs）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（AAb+）和多个胰岛自身抗体阳性（AAb+）患者的胰腺体积。 AAb+和AAb-T1D一级亲属（FDR），以评估其预后效用。在此，我们建议增加 评价该互补群体中的血清和粪便外分泌功能标志物，以评价其 预后效用和确定外分泌丧失的时间（目的1B）。我们假设外分泌标记物 在T1D第1阶段之前，在那些注定进展的患者中降低，并且其下降速率可用于 预测疾病发作。最后，T1D患者胰腺外分泌质量和功能降低的潜在机制 目前尚不清楚;主要的假设包括缺乏胰岛素分泌或对外分泌组织的自身免疫， 胰腺萎缩本研究的次要目的将使用来自胰腺癌网络的样本。 糖尿病器官捐献者（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（目的2）。我们假设存在外分泌自身免疫 在多个胰岛AAb+受试者和临床T1D受试者中，导致外分泌质量减少， 功能我们假设胰岛素减少症存在于临床T1D患者中，并导致进一步的外分泌 萎缩如果我们的假设被证实，这将代表我们对人类行为的传统理解的范式转变。 T1D作为内分泌特异性自身免疫性疾病的发病机制。这个提议会促进我早期的事业 目的是更好地了解T1D胰腺外分泌变化的时间和作用，并将这些知识应用于 预防和干预试验。本研究建议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 在1）人类受试者研究试验设计、实施和分析2）生物标志物方面的联盟和培训 3）转化科学设计与技术。合作融洽，优秀的指导， 和使命培训下一代的调查人员在整个佛罗里达大学研究所和 部门为职业成功提供了理想的环境。