Diabetes Genome Anatomy Project (DGAP)

描述(由申请人提供)：糖尿病基因组解剖计划(DGAP)代表了一项新的倡议，旨在揭示胰岛素作用、胰岛素抵抗和II型糖尿病遗传学之间的联系。该项目是与NIDDK联合开发的，是对糖尿病研究工作组报告的回应，并以生物工程、生物成像和生物信息学研究伙伴关系(BRP)的形式提出，代表了来自五个机构的研究人员的努力。有六个项目和四个核心构成一个高度互动的矩阵，也是建立未来项目或与相关项目和赠款互动的一个脚手架。该项目的总体目标是确定参与胰岛素作用的基因和基因产物的集合，以及2型糖尿病的易感性，以及因糖尿病代谢异常而发生的基因表达的继发性变化。涉及人类和啮齿动物组织的五个主要项目和一个试点项目将使我们能够：(1)创建一个数据库，其中包括受胰岛素、胰岛素抵抗和糖尿病调节的胰岛素反应组织以及淋巴细胞等可接触组织中表达的基因。(2)评估正常和转基因啮齿类动物、正常、胰岛素抵抗和糖尿病人类以及培养和新鲜分离的细胞模型中胰岛素刺激前后每个组织中基因表达的水平和模式。(3)在mRNA和/或蛋白质水平上的表达水平和模式与动物或细胞的遗传和代谢表型相关。(4)从一组2型糖尿病患者中产生基因组序列，重点放在受胰岛素和糖尿病最高调控的基因上，以确定这些基因及其编码的蛋白质的序列和表达变异的范围，这些基因可能影响糖尿病或胰岛素抵抗的风险。所产生的信息将被用于创建一个高度注释和互动的公共数据库，用于基因表达和蛋白质组分析的标准化协议，并最终为该领域的研究人员创建特定于糖尿病和特定于胰岛素的DNA芯片。 通过这种方式，我们建议定义基因表达的正常解剖(即基础水平的表达和对胰岛素的反应)、基因表达的病态解剖(即糖尿病对表达模式和胰岛素反应的影响)以及遗传变异可能在多大程度上导致表达的变化或糖尿病本身。这将有助于所有研究人员揭开胰岛素作用的复杂性及其在糖尿病中的变化，并最终帮助开发出更有效和具体的疾病分类、代谢分期和治疗模式。

DESCRIPTION (provided by applicant): The Diabetes Genome Anatomy Project (DGAP) represents a new initiative in unraveling the interface between insulin action; insulin resistance and the genetics of type II diabetes. The project was developed in conjunction with NIDDK and in response to the report of the Diabetes Research Working Group, and is presented in the form of a Bioengineering, Bioimaging, and Bioinformatics Research Partnership (BRP), representing the efforts of investigators from five institutions. There are six projects and four cores that form a highly interactive matrix and also serve as a scaffold on which to build future projects or interactions with related projects and grants. The overall goal of the project is to identify the sets of the genes and gene products involved in insulin action and the predisposition to type 2 diabetes, as well as the secondary changes in gene expression that occur in response to the metabolic abnormalities present in diabetes. There are five major and one pilot project involving human and rodent tissues that will allow us to: (1) Create a database of the genes expressed in insulin-responsive tissues, as well as accessible tissues such as lymphocytes, that are regulated by insulin, insulin resistance and diabetes. (2) Assess levels and patterns of gene expression in each tissue before and after insulin stimulation in normal and genetically-modified rodents; normal, insulin resistant and diabetic humans, and in cultured and freshly isolated cell models. (3) Correlate the level and patterns of expression at the mRNA and/or protein level with the genetic and metabolic phenotype of the animal or cell. (4) Generate genomic sequence from a panel of humans with type 2 diabetes focusing on the genes most highly regulated by insulin and diabetes to determine the range of sequence and expression variation in these genes and the proteins they encode, which might affect the risk of diabetes or insulin resistance. The resultant information will be used to create a highly annotated and interactive public database, standardized protocols for gene expression and proteomic analysis, and ultimately diabetes-specific and insulin action-specific DNA chips for investigators in the field. In this manner, we propose to define the normal anatomy of gene expression (i.e. basal levels of expression and response to insulin), the morbid anatomy of gene expression (i.e., the impact of diabetes on expression patters and the insulin response) and the extent to which genetic variability might contribute to the alterations in expression or to diabetes itself. This will aid all investigators in the quest to unravel the complexity of insulin action and its alterations in diabetes, and ultimately help develop more effective and specific modes for classification, metabolic staging and therapy of the disease.