COLLAGEN GENE REGULATION IN DEVELOPMENT AND DISEASE

描述：（改编自申请人的摘要）-I型胶原蛋白， 脊椎动物中含量最丰富的蛋白质，具有多种生物学功能， 包括为结缔组织提供拉伸强度，形成 所有主要内脏器官中结缔组织的框架，并促进 细胞在发育过程中的迁移和分化。 因此， (but仍然缺乏）基因表达调控的知识 编码I型胶原蛋白对于理解这些不同的 以及可能影响它们的疾病。 申请人有长期 和成功的跟踪记录，分析5'侧翼序列的 a1（I）胶原基因。 正如申请人指出的，许多研究 试图解决细胞特异性调节表达的I型 胶原基因，但这些机制仍然不清楚。 特别是 a1（I）胶原基因和染色质远端元件的作用 结构未知。 因此，该提案的长期目标是 在分子水平上理解，参与的复杂机制， 阶段和a1（I）胶原基因的组织特异性调节。 的 申请人提出实现分析染色质的作用的目标 结构和核基质中a1（I）胶原表达的调控。 五个具体目标是： 因为细胞中高水平的a1（I）胶原蛋白产生大量的 I型胶原蛋白;识别和分析参与的调节元件， a1（I）胶原结构域的染色质环组织;分析 转基因小鼠远端调控元件的功能;分析a1（I） 正常发育和分化中的调节元件， 纤维化疾病

DESCRIPTION: (Adapted from the applicant's abstract) - Type I collagen, the most abundant protein in vertebrates, has diverse biologic function, including providing tensile strength to connective tissues, forming the framework of connective tissue in all major internal organs, and promoting cell migration and differentiation during development. Thus, a detailed (but still lacking) knowledge of the regulation of expression of the genes encoding type I collagen is essential for understanding these various processes and the diseases that can affect them. The applicant has a long and successful track record in analyzing the 5' flanking sequence of the a1(I) collagen gene. As the applicant points out, numerous studies have tried to address the cell-specific regulation of expression of the type I collagen genes yet these mechanisms are still not understood. In particular the role of distal elements in the a1(I) collagen gene and of the chromatin structure is unknown. Thus, the long-term goal of this proposal is to understand at the molecular level, the complex mechanisms involved in the stage and tissue-specific regulation of the a1(I) collagen gene. The applicant proposes to achieve this goal of analyzing the role of chromatin structure and the nuclear matrix in a1(I) collagen regulation of expression. The five specific aims are: To identify regulatory elements that account for the high level of a1(I) collagen in cells that produce large amounts of type I collagen; to identify and analyze regulatory elements involved in the chromatin loop organization of the a1(I) collagen domain; to analyze the functions of distal regulatory elements in transgenic mice; to analyze a1(I) regulatory elements in normal development and differentiation and in fibrotic disorders.