MOLECULAR DETERMINANTS OF NERVE GROWTH AND REPAIR

神经生长和修复的分子决定因素

• 批准号: 2269288
• 负责人: MICHAEL J IGNATIUS
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 1997-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2269288
• 关键词: cell adhesion; cell growth regulation; chick embryo; extracellular matrix; growth cones; integrins; laminin; nervous system regeneration; neurogenesis; protein structure function; receptor binding; tissue /cell culture; video microscopy

The lack of repair within the human central nervous system remains one of the most intractable problems confronting biomedicine. Transplantation studies have shown that adult neurons can regrow substantial distances if supplied with tissue from regions of embryonic central (CNS) and peripheral (PNS) nervous system or from adult PNS, but not from adult CNS. Moreover, acellular grafts containing extracellular matrix (ECM) components can also support some regrowth. These studies emphasize that the lack of repair in the adult CNS is due to the absence of the appropriate environment for growth rather than an inherent deficit of CNS neurons. A cellular and molecular approach is proposed here to characterize one neuronal receptor system that can support neurite outgrowth during development and regeneration. One prominent component of the acellular environment is laminin (LN), a potent stimulator of neuronal process outgrowth from CNS and PNS neurons. LN is abundantly expressed in developing CNS and PNS fiber tracts yet in the adult is only present in the PNS. This grant proposal is focused on one of the major receptor systems for LN expressed on the surface of neuronal growth cones - integrins - and in particular on one experimentally advantageous member of this gene family: the integrin alpha1/beta1, a LN receptor. The experiments proposed here are designed to elucidate (i) the structural determinants by which the alpha1/beta1 integrin binds to extracellular matrix ligands, with particular focus on how in different cell types this integrin binds to a different repertoire of ligands; and (ii) how this receptor and associated proteins function during growth cone extension in defined environments in vitro. A combination of molecular, biochemical, immunological, cell culture, and video microscopy techniques will be used to determine the function of alpha1/beta1 integrins in promoting and sustaining nerve growth. Defining the molecular determinants of nerve growth and repair may help in creating a permissive environment for the growth of adult neurons in clinical paradigms of repair, as well as slowing the progress of neurodegenerative disease.

人类中枢神经系统中缺乏维修仍然是 在生物医学面临的最棘手的问题中。 移植研究表明，成年神经元可以再生 如果从胚胎区域提供组织，则很大的距离 中央（CNS）和周围（PNS）神经系统或成年PNS，但 不是来自成人中枢神经系统。 此外，包含细胞外的细胞移植 矩阵（ECM）组件也可以支持一些再生。 这些研究 强调成人中枢神经系统缺乏维修是由于缺席 适当的增长环境，而不是固有的赤字 CNS神经元。 这里提出了细胞和分子方法 表征一个可以支持神经突的神经元受体系统 发展和再生期间的生长。 细胞环境的一个突出组成部分是层粘连蛋白（LN），A 来自中枢神经系统和PNS神经元的神经元过程生长的有效刺激剂。 LN在开发CNS和PNS纤维区域中大量表达 成人仅存在于PNS中。 该赠款提案的重点是 LN表面表达的LN的主要受体系统之一 神经元生长锥 - 整合素 - 尤其是一个 该基因家族的实验有利成员：整合素 alpha1/beta1，LN受体。 这里提出的实验是设计的 阐明（i）alpha1/beta1的结构决定因素 整联蛋白与细胞外基质配体结合，特别关注 在不同的细胞类型中，该整合素如何与不同的曲目结合 配体； （ii）该受体和相关蛋白如何功能 在体外定义环境中的生长锥扩展过程中。 一个 分子，生化，免疫学，细胞培养和 视频显微镜技术将用于确定 alpha1/beta1整联蛋白在促进和维持神经生长方面。 定义神经生长和修复的分子决定因素可能有助于 在为成年神经元增长的宽松环境中 修复的临床范式，并减慢 神经退行性疾病。