COLLAGEN GENE REGULATION IN DEVELOPMENT AND DISEASE

描述：(改编自申请人的摘要)-I型胶原， 脊椎动物中最丰富的蛋白质，具有不同的生物功能， 包括为结缔组织提供抗拉强度，形成 结缔组织在所有主要脏器的框架，并促进 细胞在发育过程中的迁移和分化。因此，一个详细的 (但仍然缺乏)对基因表达调控的知识 编码I型胶原对于理解这些不同的 以及可能影响这些过程的疾病。申请者有很长一段时间 并成功地分析了该基因5‘侧翼序列 A1(I)胶原基因。正如申请者指出的那样，许多研究已经 试图解决I型基因表达的细胞特异性调控 胶原蛋白基因，但这些机制仍不清楚。特别是 A1(I)胶原基因远端元件和染色质的作用 结构未知。因此，这项提议的长期目标是 在分子水平上理解，涉及的复杂机制 A1(I)胶原基因的阶段和组织特异性调节。这个 申请人建议实现这一目标，分析染色质的作用 结构和核基质中A1(I)胶原蛋白的表达调控。 五个具体目标是：确定监管要素，以说明 对于细胞中高水平的A1(I)胶原产生大量 I型胶原蛋白；鉴定和分析参与 A1(I)胶原区的染色质环组织；分析 远端调控元件在转基因小鼠中的功能分析A1(I) 正常发育和分化中的调控因素 纤维性疾病。

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.