GENOMICS AND PROTEOMICS OF CELL INJURY AND INFLAMMATION

细胞对损伤和炎症的反应是 人类的几种主要疾病。在这项提案中，调查人员将寻求 为了阐明这些反应背后的基本机制 基因组学和蛋白质组学相结合的方法将反应连接到 涉及的基因和蛋白质。就本提案而言，伤害是 在最广泛的意义上定义，并将包括不同的，临床相关， 致病刺激。该提案包括四个主要步骤。首先， 研究人员将使用基于微阵列的方法来识别主要基因 参与选定的细胞类型对明确的炎症性或 有害的刺激。其次，研究人员将对这些基因进行DNA筛选 序列多态。临床选择的其他候选基因 标准或通过多态预测算法也将被筛选。 第三，调查人员将进行关联研究，以评估 这些基因多态性的临床意义。第四，调查人员将 开发用于执行功能的试剂(抗体和多肽) 对这些基因中选定的一个子集的研究。该计划的组织形式是 线性步骤序列，其中一个项目的输出提供 为下一步的项目奠定了实验基础。由于每个项目都由 前一个项目的成果，综合产量的累计 基因组应用程序(PGA)的价值远远超过其应有的价值 由每个项目单独实现。这部剧的中心生物学主题是 计划是炎症和组织重塑，将在 心血管疾病的临床背景。有一个强有力的理由来支持 这一特别的重点，基于四个基本考虑。第一, 炎症和组织重塑是与许多相关的生物过程 临床疾病。尽管这些过程的选定特征可以是 对于给定的组织或疾病背景，其他方面将被证明是 万能的。因此，为等位基因分型和功能 对多态基因产生的基因产品的评估将发现广泛的 在心、肺、血液研究中的应用。第二，通过学习 心血管疾病特定背景下的炎症和组织重塑 疾病，研究人员攻击那些代表领先的疾病 当今美国人死亡和残疾的原因。第三，这一点 Focus将允许调查人员放大由以下机构提供的资金的影响 PGA，通过将这一提议与最近资助的雷诺赠款联系起来， 西南地区将提供独特的组织重塑是复杂的 最适合基因组规模方法的生物过程。这个 因此，PGA的目标和实验设计与 RFA征集。

The cellular response to injury and inflammation is a fundamental component of several major human diseases. In this proposal, the investigators will seek to elucidate the basic mechanisms underlying these responses through a combination of genomic and proteomic approaches linking the responses to the genes and proteins involved. For the purposes of this proposal, injury is defined in the broadest sense and will encompass diverse, clinically relevant, pathogenic stimuli. The proposal encompasses four major steps. First, the investigators will use microarray-based methods to identify major genes involved in the responses of selected cell types to defined inflammatory or injurious stimuli. Second, the investigators will screen these genes for DNA sequence polymorphisms. Additional candidate genes selected by clinical criteria or by a polymorphism prediction algorithm will also be screened. Third, the investigators will perform association studies to assess the clinical significance of these polymorphisms. Fourth, the investigators will develop reagents (antibodies and peptides) with which to perform functional studies of a selected subset of these genes. The program is organized as a linear sequence of steps, in which the output from one project provides an experimental basis for the following project. Since each project is guided by the results of the preceding project, the cumulative output of the integrated Program in Genomic Applications (PGA) is far more valuable than what could be achieved by each project in isolation. The central biological theme of the program is inflammation and tissue remodeling, to be studied explicitly in the clinical context of cardiovascular disease. There is a strong rationale for this particular focus, based on four fundamental considerations. First, inflammation and tissue remodeling are biological processes pertinent to many clinical disorders. Although selected features of these processes may be unique to a given tissue or disease context, other aspects will prove to be universal. Thus, reagents developed for allelotyping and functional assessment of gene products produced from polymorphic genes will find broad application in heart, lung and blood research. Second, by studying inflammation and tissue remodeling in the specific context of cardiovascular diseases, the investigators attack those conditions that represent leading causes of death and disability among Americans today. Third, this particular focus will allow the investigators to amplify the impact of funds provided by the PGA, by linking this proposal to the recently funded Reynolds grant to Southwestern that will provide a unique tissue remodeling are complex biological processes that are ideally suited to a genomic scale approach. The aims and experimental design of this PGA are therefore highly congruent with the RFA solicitation.