Pathobiology of the Enteric System

 描述(由申请者提供)：这项计划项目拨款专注于了解糖尿病胃轻瘫的基本机制，并立即将这些发现转化为我们患者的新治疗方案。这一点很重要，因为目前的治疗 我们对糖尿病胃轻瘫患者的治疗方法大多无效。这个高生产率的计划项目围绕3个项目和3个核心进行组织，形成一个紧密集成的计划项目。我们将通过利用所有三个项目中的尖端发现工作，并使这些发现在项目3中立即应用于临床，来实现项目项目的总体目标。项目1利用包括下一代测序在内的各种创新工具来确定导致糖尿病胃轻瘫患者出现不同细胞变化的常见统一性异常。初步数据表明，巨噬细胞在糖尿病胃轻瘫的发生发展中起关键作用，巨噬细胞亚型和血红素加氧酶1途径的调节可以逆转细胞损伤，使胃功能恢复正常。项目2将利用以下状态 ART工具专注于神经元型一氧化氮合酶(NOS1，nNOS)的表观遗传控制。NOS1表达的组织水平降低是所描述的糖尿病肠神经病变的第一种特殊形式。项目2将研究由骨形态发生蛋白(BMP)-Smad-EP300/CREBBP组蛋白乙酰转移酶(HATS)、低氧诱导因子1a(HIF1a)-EP300/CREBBP HATS和胰岛素/胰岛素样生长因子1(Igf1)-Ezh2组蛋白甲基转移酶组成的转录/表观遗传网络，并提出该网络调节健康和糖尿病胃轻瘫中NOS1表达的神经元池。项目3将继续侧重于了解糖尿病胃排空障碍的机制，并为这种情况开发高度新颖的管理方法，包括临床试验。这些项目得到了同样尖端的核心的支持。核心A将提供行政支持。核心B将通过提供CHIP-SEQ、RNA-SEQ和DNA甲基化专门知识以及第三级生物信息学分析，支持所有三个项目开展的表观基因组和转录实验。作为一个生理特征和数据集成核心，Core C将为所有三个项目提供服务，包括进行小鼠的胃排空和血糖分析以及人类活体组织的粘膜离子通量分析，维护电子动物研究记录，以及开发和维护一个整合计划项目中收集的数据的平台。这一高度集成、协同和协作的计划项目将机械地确定糖尿病胃轻瘫的潜在病理生物学，并利用这些信息在非常短的床边到患者的时间框架内设计和测试患者的治疗方法。

 DESCRIPTION (provided by applicant): This Program Project grant focuses on understanding the basic mechanisms that underlie diabetic gastroparesis and immediately translating those findings into new therapeutic solutions for our patients. This is important, as current therapeutic approaches for our patients with diabetic gastroparesis are largely ineffective. This highly productive Program Project is organized around 3 projects and 3 cores resulting in a tightly integrated Program Project. We will accomplish the overall objective of the Program Project by taking advantage of the cutting edge discovery work in all three Projects and making these discoveries immediately clinically relevant in Project 3. Project 1 utilizes a wide variety of innovative tools including next generation sequencing to determine the common unifying abnormality that leads to the diverse cellular changes seen in diabetic gastroparesis. Preliminary data suggest that macrophages are key to the development of diabetic gastroparesis and that modulation of macrophage subtypes and the heme oxygenase 1 pathway can reverse cellular injury and normalize gastric function. Project 2 will utilize state of the art tools to focus on the epigenetic control of neuronal nitric oxide synthase (Nos1, nNOS). Tissue-level reduction in Nos1 expression was the first specific form of diabetic enteric neuropathy described. Project 2 will examine a transcriptional/epigenetic network consisting of bone morphogenetic protein (Bmp)-Smad-Ep300/Crebbp histone acetyltransferases (HATs), hypoxia-inducible factor 1a (Hif1a)-Ep300/Crebbp HATs and insulin/insulin-like growth factor 1 (Igf1)-Ezh2 histone methyltransferase and proposes that this network regulates the pool of Nos1-expressing neurons in health and diabetic gastroparesis. Project 3 will continue to focus on understanding the mechanisms responsible for gastric emptying disturbances in diabetes and on developing highly novel management approaches for this condition including clinical trials. The Projects are supported by equally cutting edge cores. Core A will provide administrative support. Core B will support the epigenomic and transcriptomic experiments carried out by all three Projects by providing ChIP-seq, RNA-seq and DNA methylation expertise and tertiary bioinformatics analysis. Core C as a Physiological Characterization and Data Integration Core will provide service for all three Projects by performing gastric emptying and blood glucose assays in mice and mucosal ion flux in human biopsies, maintaining an Electronic Animal Research Record and developing and maintaining a platform for the integration of data collected in the Program Project. Together this highly integrated, synergistic and collaborative Program Project will mechanistically determine the underlying pathobiology of diabetic gastroparesis and use this information to devise and test therapies in patients in a very short bedside to patient time frame.