PATHOPHYSIOLOGY OF FIBRILLAR COLLAGEN TYPES

纤维状胶原类型的病理生理学

• 批准号: 2079331
• 负责人: Francesco B Ramirez
• 金额: $ 31.71万
• 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/2079331
• 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.

发育和成熟器官系统的机械性能是 主要由原纤维胶原蛋白的沉积确定 细胞外基质。 这得出了这些结构缺陷 大分子会导致遗传的主要遗传条件，从而产生不利影响 身体器官的完整性。 除了它们的支持功能， 胶原蛋白在许多发展程序中也起着动态的作用 和生理过程，例如组织重塑和伤口愈合。 放松管制的胶原蛋白生物合成是几种病理的标志 疾病，包括纤维化，炎症和关节炎。 这是 该应用的长期目标是阐明机制 潜在的胶原蛋白病理生理学。 为此，两项重大研究 提出了主题。 第一个将探索胶原突变的表型后果 人类状况和转基因小鼠。 第二个会破译 需要胶原蛋白生物合成的分子电路。 具体而言，我们将表征II型胶原蛋白突变 软骨发育异常患者确认并延长遗传和临床 了解这种胶原症。 我们将利用转基因鼠标 建立小纤维的功能和发病机理的模型 胶原蛋白类型。 我们将采用转染实验和DNA：蛋白质 结合测定法，以识别控制的调节元素 胶原基因的表达。 最后，我们将克隆编码的基因 调节胶原蛋白表达的跨作用因子。 这项工作的目的是更好地理解结缔组织 与组织病理学有关 纤维胶原类型。