Interrogating beta cell function and heterogeneity of C-peptide preservation in patients with type 1 diabetes or chronic pancreatitis

项目总结/摘要： 1型糖尿病（T1 D）是一种日益加重的公共卫生负担，目前的治疗方法主要集中在胰岛素上 更换.未来的T1 D治疗将尝试在新发T1 D患者中保留内源性胰腺β细胞功能。 T1 D和通过移植替代长期糖尿病的β细胞。传统上，T1 D被视为 自身免疫性疾病，但β细胞损失也由遗传风险因素和代谢压力驱动。了很多 已经尝试延迟T1 D从临床前多种自身抗体阳性进展为临床疾病，但 发展是高度异质的。C肽保存可改善糖尿病控制并降低风险 治疗糖尿病并发症有一系列广泛的C-肽测量来检查内源性β 细胞功能和应激，并且许多基因与T1 D中的C肽保存相关。少即是 已知遗传学对部分移植过程中内源性β细胞功能保留的影响， 缓解期（PRM）或诊断后的“蜜月期”。这些因素对于患有以下疾病的患者也可能很重要： 慢性胰腺炎（CP），有胰岛丢失风险，但遗传风险和代谢应激源仍然存在 大部分未开发。CP患者由于持续性内分泌失调而出现剧烈疼痛和进行性内分泌功能不全。 炎症和肝脏胰岛素抵抗。对于重症CP患者，全胰切除联合胰岛自体移植是一种有效的治疗方法。 移植（TPIAT）是一种尝试，以保留患者的内源性β细胞功能，同时去除患者的内源性β细胞。 他们痛苦的根源。移植期间年龄较小和β细胞量较高是功能性 移植物存活率关于β细胞遗传学在这些患者中的作用知之甚少，我将在本文中评估。 提议 我是一个新兴的研究人员，在基础科学β细胞研究和临床研究定义的经验， T1 D的异质性。我在这个职业发展奖的目标是通过学习磨练临床研究技能 在新诊断的T1 D患者和T1 D模型中， 细胞治疗（已接受TPIAT的CP患者），目的如下： 1：分析β细胞功能和应激的基线标志物是否可以预测PRM C肽保存。 2：评估已知的预先指定的T1 D SNP是否与PRM C肽保留相关 3：评估与C肽保存相关的预先指定的SNP是否预测胰岛素使用和C肽在胰岛素中的作用。 接受TPIAT的CP患者 作为K23奖项提案的一部分，我概述了支持我的教育，培训和科学目标。 通往独立的道路。我已经组建了一个多元化和广泛的导师/合作者团队来支持这一点 奋进。这个职业发展奖将支持我的职业目标，阐明β细胞的异质性， （dys-）功能，并开发新的细胞治疗干预。

PROJECT SUMMARY/ABSTRACT: Type 1 diabetes (T1D) is an increasing public health burden for which current therapies are focused on insulin replacement. Future T1D treatments will try to preserve endogenous pancreatic beta cell function in new onset T1D and replace beta cells via transplantation in long standing diabetes. Classically, T1D is viewed as an autoimmune disease but beta cell loss is also driven by genetic risk factors and metabolic stress. Much has been done to try to delay T1D progression from preclinical multiple autoantibody positivity to clinical disease, but progression is highly heterogenous. C-peptide preservation can improve diabetes control and decrease the risk for diabetes complications. There are a wide array of C-peptide measurements to examine endogenous beta cell function and stress and many genes have been associated with C-peptide preservation in T1D. Less is known about the influence of genetics on the preservation of endogenous beta cell function during the partial remission period (PRM) or “honeymoon” after diagnosis. These factors are also likely important for patients with chronic pancreatitis (CP) who have risk for islet loss but for whom genetic risk and metabolic stressors remain largely unexplored. Patients with CP have severe pain and progressive endocrine insufficiency due to persistent inflammation and hepatic insulin resistance. For patients with severe CP, total pancreatectomy with islet auto- transplantation (TPIAT) is an attempt to preserve a patient’s endogenous beta cell function while removing the source of their pain. Younger age and higher beta cell mass during transplantation are predictors for functional graft survival. Less is known about the role of beta cell genetics in these patients, which I will evaluate in this proposal. I am an emerging researcher with experience in basic science beta cells studies and clinical research defining heterogeneity in T1D. My goal in this career development award is to hone clinical research skills by studying the impact of genetics and markers of beta cell function in patients with newly diagnosed T1D and in a model of cell therapy (CP patients who have undergone TPIAT) with these aims: 1: Analyze if baseline markers of beta cell function and stress can predict PRM C-peptide preservation. 2: Evaluate if known pre-specified T1D SNPs are associated with PRM C-peptide preservation 3: Evaluate if pre-specified SNPs associated with C-peptide preservation predict insulin use and C-peptide in CP patients who have undergone TPIAT As part of this K23 award proposal, I outline educational, training, and scientific goals that will support my pathway to independence. I have assembled a diverse and broad mentorship/collaborator team to support this endeavor. This career development award will support my career goal to elucidate heterogeneity in beta cell (dys-)function in diabetes and to develop novel cell therapy interventions.