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

项目摘要/摘要： 1型糖尿病(T1D)是一种日益加重的公共健康负担，目前的治疗方法主要是胰岛素 替补。未来的T1D治疗将试图在新的发病中保留内源性胰岛β细胞功能 通过移植治疗长期糖尿病患者的T1D和替换β细胞。传统上，T1D被视为 自身免疫性疾病，但β细胞丢失也是由遗传风险因素和新陈代谢压力驱动的。很多都有 试图延缓T1D从临床前多种自身抗体阳性到临床疾病的进展，但 进展是高度异质性的。保存C-肽可改善糖尿病控制，降低风险 治疗糖尿病并发症。有各种各样的C-肽测量来检查内源性的β- 细胞功能和应激以及许多基因与T_1D中C-肽的保存有关。更少就是 已知遗传学对部分性腺样囊性贫血时内源性β细胞功能保存的影响 确诊后的缓解期(PRM)或“蜜月期”。这些因素也可能对患有 慢性胰腺炎(CP)有胰岛丢失的风险，但遗传风险和代谢应激源仍然存在 很大程度上是未被开发的。CP患者因持续性疼痛和进行性内分泌功能不全 炎症和肝脏胰岛素抵抗。重症慢性胰腺炎患者行自体胰岛全切除 移植(TPIAT)是一种试图保留患者内源性β细胞功能的方法，同时移除 他们的痛苦之源。移植期间年龄较小和较高的β细胞质量是功能性 移植物存活率。对β细胞遗传学在这些患者中的作用知之甚少，我将在本文中进行评估。 求婚。 我是一名新兴的研究人员，在基础科学、β细胞研究和临床研究方面有丰富的经验 T1D的异质性。我在这个职业发展奖中的目标是通过学习磨练临床研究技能 遗传学和β细胞功能标记物对新诊断的T1D患者和T1D模型的影响 细胞治疗(接受过TPIAT的慢性阻塞性肺病患者)，目的如下： 1：分析胰岛β细胞功能和应激的基线标志物是否能预测PRM C肽的保存。 2：评估已知的预先指定的T1D SNP是否与PRM C肽保存相关 3：评估与C-肽保存相关的预先指定的SNPs是否预测胰岛素的使用和C-肽在 接受TPIAT的慢性阻塞性肺疾病患者 作为K23奖励计划的一部分，我概述了教育、培训和科学目标，这些目标将支持我的 通向独立的道路。我已经组建了一个多样化和广泛的导师/合作者团队来支持这一点 努力吧。这个职业发展奖将支持我的职业目标，即阐明β细胞的异质性。 (DYS-)在糖尿病中的作用，并开发新的细胞治疗干预措施。

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.