PATHOPHYSIOLOGY OF HUMAN FIBRILLAR COLLAGEN TYPES

人类纤维胶原类型的病理生理学

• 批准号: 3158684
• 负责人: Francesco B Ramirez
• 金额: $ 27.96万
• 依托单位: MOUNT SINAI SCHOOL OF MEDICINE OF CUNY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3158684
• 关键词: achondroplasia; affinity chromatography; athymic mouse; autoradiography; chondrodystrophy; collagen; developmental genetics; extracellular matrix proteins; gel electrophoresis; gene expression; gene mutation; genetic regulatory element; genetic transcription; genetically modified animals; molecular cloning; nucleic acid sequence; procollagen; protein biosynthesis; transcription factor; transfection

The mechanical properties of developing and mature organ systems are primarily determined by the deposition of fibrillar collagens in the extracellular matrix. It follows that structural defects in these macromolecules cause dominantly inherited conditions that adversely affect the integrity of bodily organs. In addition to their supportive function, collagens also play a dynamic role in a number of developmental programs and physiological processes, such as tissue remodeling and wound healing. Deregulated collagen biosynthesis is the hallmark of several pathological conditions, including fibrotic, inflammatory and arthritic diseases. It is the long-term goal of this application to elucidate the mechanisms underlying collagen pathophysiology. Toward this end, two major research themes are proposed. The first will explore the phenotypic consequences of collagen mutations in human conditions and in transgenic mice. The second will decipher the molecular circuitries that require collagen biosynthesis. Specifically, we will characterize type II collagen mutations in chondrodysplastic patients to confirm and extend the genetic and clinical understanding of this collagenopathy. We will utilize the transgenic mouse model to establish the function and pathogenesis of minor fibrillar collagen types. We will employ transfection experiments and DNA:protein binding assays to identify cis-acting regulatory elements that control the expression of collagen genes. Finally, we will clone the genes encoding the trans-acting factors that regulate collagen expression. The thrust of this work is to achieve a better understanding of connective tissue pathology as it relates to the function and biosynthesis of fibrillar collagen types.

发育中和成熟器官系统的机械特性是 主要由纤维状胶原蛋白的沉积决定 细胞外基质。 由此可见，这些结构缺陷 大分子会导致显性遗传疾病，从而产生不利影响 身体器官的完整性。 除了它们的辅助功能外， 胶原蛋白还在许多发育计划中发挥着动态作用 和生理过程，例如组织重塑和伤口愈合。 胶原蛋白生物合成失调是多种病理学的标志 疾病，包括纤维化、炎症和关节炎疾病。 这是 本申请的长期目标是阐明其机制 潜在的胶原蛋白病理生理学。 为此，两项主要研究 提出了主题。 第一个将探讨胶原蛋白突变的表型后果 人类条件和转基因小鼠。 第二个将破译 需要胶原蛋白生物合成的分子电路。 具体来说，我们将表征 II 型胶原突变 软骨发育不良患者确认并扩展遗传和临床 了解这种胶原病。 我们将利用转基因小鼠 建立小原纤维功能和发病机制的模型 胶原蛋白类型。 我们将采用转染实验和DNA：蛋白质 结合测定来识别控制的顺式作用调节元件 胶原基因的表达。 最后，我们将克隆编码基因 调节胶原蛋白表达的反式作用因子。 这项工作的主旨是更好地理解连接 组织病理学，因为它与功能和生物合成有关 纤维状胶原蛋白类型。