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）历史上被描述为内分泌（β细胞）特定的自身免疫性疾病。然而， T1D诊断剂也存在胰腺大小和亚临床外分泌功能不全的降低。这 这些发现在T1D发病机理中的机制，自然历史和作用尚不清楚。外分泌萎缩 甚至可以先于某些受试者的多个胰岛自动抗体（阶段1 T1D）的发作，签名 外分泌质量和功能的临床测量可能是早期T1D生物标志物。主要目标 该提议的是建立T1D前外分泌损失的自然历史，并确定外分泌T1D- 预测生物标志物。我们将测量粪便弹性酶（FE-1），这是外分泌功能的临床标记， 泰迪（Teddy 样品（AIM 1A）。一项由R01资助的试验网（TN）受试者（Campbell-Thompson and Haller， MPI）可能会检查单胰岛自身抗体阳性（AAB+）中MRI的胰腺体积，多个 AAB+和AAB-T1D一级亲戚（FDR）评估其预后效用。我们建议在此添加 评估该完整人群中的血清和粪便外分泌功能标记，以评估其 预后效用并确定外分泌损失的时机（AIM 1B）。我们假设外分泌标记将是 在阶段1 T1D之前降低了那些注定要进行进展的人，他们的下降速度可以用来 预测疾病发作。最后，降低的外分泌胰腺质量和功能的机制在T1D中的功能 保持不清楚；主要的假设包括缺乏胰岛素分泌或自身免疫性到外分泌组织 胰腺萎缩。这项研究的次要目标将使用网络中的样品进行胰腺 具有糖尿病（NPOD）队列的器官供体研究这些潜在机制并评估外分泌 胰腺自身抗体作为风险的生物标志物（AIM 2）。我们假设存在外分泌自身免疫性 在具有多个胰岛AAB+和临床T1D的受试者中，外分泌质量和 功能。我们假设患有临床T1D的患者存在胰岛素症，并导致进一步的外分泌 萎缩。如果我们的假设得到证明，这将代表我们对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理。该提议将发展我的早期职业 目标是更好地了解T1D外分泌胰腺的时机和作用，并将这些知识应用于 预防和干预试验。该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，并在几项大型T1D研究中包括合作 1）人类受试者研究试验设计，实施和分析2）生物标志物的财团和培训 评估和3）翻译科学设计和技术。协作融洽的融洽关系，出色的心态， 以及培训佛罗里达大学研究所的下一代调查人员的任务 部门为职业成功提供了理想的环境。