Pathobiology of the Enteric System

肠道系统病理学

• 批准号: 9518831
• 负责人: ADIL E. BHARUCHA
• 金额: $ 198.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9518831
• 关键词: Advisory Committees; Animal Experimentation; Animals; Bioinformatics; Biological Assay; Biopsy; Blood Glucose; Bone Morphogenetic Proteins; Budgets; ChIP-seq; Chronic; Clinic; Clinical; Clinical Trials; Communication; Complications of Diabetes Mellitus; DNA Methylation; Data; Data Set; Development; Diabetes Mellitus; Ensure; Enteral; Epigenetic Process; Epithelial; Extramural Activities; Functional disorder; Future; Gastric Emptying; Gastroparesis; Genetic Transcription; Health; Histone Deacetylase; Human; Hypoxia Inducible Factor; Insulin; Insulin-Like Growth Factor I; Intestines; Ions; Journals; Lead; Manuscripts; Mediating; Methylation; Molecular; Mucous Membrane; Mus; Neurons; Neuropathy; Nitric Oxide Synthase Type I; Pathway interactions; Patient Care; Patients; Phenotype; Physiological; Physiology; Preparation; Program Research Project Grants; Publications; Publishing; Running; Services; Smad Proteins; Small Intestines; Stomach; Supervision; Symptoms; System; Testing; Therapeutic; Time; Tissues; Translating; Work; cell injury; cell motility; clinically relevant; data integration; diabetic; diabetic gastroparesis; epigenetic marker; epigenomics; experimental study; ghrelin receptor; glucagon-like peptide 1; glycemic control; heme oxygenase-1; histone acetyltransferase; histone methyltransferase; human subject; innovation; macrophage; meetings; next generation sequencing; novel; novel therapeutics; patient subsets; programs; public health relevance; success; tool; transcriptome sequencing; transcriptomics

 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.

 描述（由申请人提供）：该计划项目拨款的重点是了解糖尿病性胃轻瘫的基本机制，并立即将这些发现转化为我们患者的新治疗解决方案。这很重要，因为目前的治疗 对于我们的糖尿病胃轻瘫患者来说，这些方法基本上是无效的。这个高效的计划项目围绕 3 个项目和 3 个核心进行组织，形成了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前沿发现工作并使这些发现在项目 3 中立即与临床相关来实现该项目的总体目标。项目 1 利用包括下一代测序在内的多种创新工具来确定导致糖尿病胃轻瘫中出现的多种细胞变化的常见统一异常。初步数据表明，巨噬细胞是糖尿病胃轻瘫发生的关键，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并使胃功能正常化。项目2将利用状态 专注于神经元一氧化氮合酶（Nos1、nNOS）表观遗传控制的艺术工具。组织水平 Nos1 表达减少是第一个被描述的糖尿病肠神经病变的具体形式。项目 2 将检查由骨形态发生蛋白 (Bmp)-Smad-Ep300/Crebbp 组蛋白乙酰转移酶 (HAT)、缺氧诱导因子 1a (Hif1a)-Ep300/Crebbp HAT 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，以及 提出该网络调节健康和糖尿病胃轻瘫中表达 Nos1 的神经元库。项目 3 将继续致力于了解糖尿病胃排空障碍的机制，并开发针对这种情况的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。 Core B 将通过提供 ChIP-seq、RNA-seq 和 DNA 甲基化专业知识以及三级生物信息学分析来支持所有三个项目进行的表观基因组和转录组实验。核心 C 作为生理表征和数据集成核心，将为所有三个项目提供服务，包括在小鼠中进行胃排空和血糖测定以及在人体活检中进行粘膜离子通量分析，维护电子动物研究记录以及开发和维护用于集成计划项目中收集的数据的平台。这个高度集成、协同和协作的项目将机械地确定糖尿病胃轻瘫的潜在病理学，并利用这些信息在很短的床边时间范围内设计和测试患者的治疗方法。