COLLAGEN GENES IN HERITABLE CONNECTIVE TISSUE DISORDERS

遗传性结缔组织疾病中的胶原蛋白基因

• 批准号: 3085583
• 负责人: Clair A. Francomano
• 金额: $ 7.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3085583
• 关键词: Marfan syndrome; alleles; biological polymorphism; chondrodystrophy; collagen; collagen disorder; connective tissue disorder; electrophoresis; gene expression; gene frequency; gene mutation; human tissue; linkage mapping; messenger RNA; molecular cloning; nucleic acid probes; nucleic acid sequence; osteoporosis; procollagen; protein biosynthesis; radiotracer

My overall goal is to acquire both the didactic training and practical laboratory experience necesary to become an independent biomedical investigator. I plan to apply this training to studies of the contribution of collagen gene alterations to a variety of hereditary disorders, including selected heritable disorders of fibrous connective tissue and chondrodystrophies. The following approaches are proposed: (1) The structure and organization of the various collagen genes in these disorders will be determined by Southern blot analysis. Unusual patterns will be compared to those seen in a panel of controls to determine if the former are the result of gross gene alterations. (2) More subtle alterations in the structure of collagen genes will be detected by linkage analysis. Large families with multiple affected individuals will be examined for cosegregation of the "mutant" phenotype and a specific collagen allele whose inheritance is detected by polymorphic restriction sites. (3) In individuals or families in whom either (1) or (2) indicates mutation in a collagen gene, studies of mRNA and protein encoded by this gene will be performed to investigate the functional significance of the gene alteration, and the mutant gene will be cloned and sequenced to demonstrate the nature of the mutation. (4) For those collagen loci for which the chromosomal assignment is unknown or unconfirmed, such assignments will be undertaken. (5) The genetic distance between the various collagen genes studies in (1)\and (2) and selected syntenic loci will be determined. The purpose of these studies is four-fold: (i) to identify and characterize mutations in the collagen genes which are responsible for certain familial disorders of connective tissues, (ii) to determine the effect of such mutations on collagen mRNA and protein synthesis and structure; (iii) to identify normal variations in the structure and organization of the collagen genes as revealed by restriction fragment length polymorphisms; (iv) to add to our knowledge of the human gene map, both in terms of the chromosomal localization of and the genetic distances between closely linked loci and the various collagen genes.

我的总体目标是获得教学培训和实用性 实验室经验必要成为独立的生物医学 研究者。 我计划将此培训应用于贡献的研究 胶原基因改变对各种遗传疾病的改变， 包括选定的纤维结缔组织遗传疾病和 软骨造成的。 提出了以下方法： （1）这些胶原基因的结构和组织 疾病将通过Southern印迹分析确定。 不寻常的模式 将与在对照组中看到的那些进行比较，以确定是否是否 前者是基因改变的结果。 （2）胶原蛋白基因结构的更多细微变化将是 通过链接分析检测。 有多个受影响的大家庭 将检查个体的“突变”表型的cosegregation 以及由多态性检测到的遗传的特定胶原蛋白等位基因 限制站点。 （3）在（1）或（2）的个人或家庭中 在胶原蛋白基因中，该基因编码的mRNA和蛋白质的研究将会 进行研究基因的功能意义 改变，突变基因将被克隆并测序以证明 突变的性质。 （4）对于那些染色体分配未知的胶原蛋白基因座 或未经证实，将进行此类任务。 （5）各种胶原基因研究之间的遗传距离 （1）\和（2）和选定的同义基因座将被确定。 这些研究的目的是四个：（i）识别和 表征胶原蛋白基因中的突变 某些结缔组织的家族疾病，（ii）确定 这种突变对胶原mRNA和蛋白质合成的影响 结构; （iii）确定结构的正常变化 限制片段揭示的胶原基因的组织 长度多态性； （iv）为了增加我们对人类基因图的了解， 在染色体定位和遗传距离方面 在紧密联系的基因座和各种胶原蛋白基因之间。