Pathophysiology of Basement Membrane Zone Collagens

基底膜区胶原蛋白的病理生理学

基本信息

批准号：
7872831
负责人：
Francesco B Ramirez
金额：
$ 33.96万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7872831
关键词：
Accounting Adipocytes Adult Architecture Basement membrane Basic Science Behavior Binding Biochemical Biochemical Genetics Biological Biomedical Research Brain hemorrhage Bulla Cardiovascular system Cell Differentiation process Cells Clinical Clinical Management Collagen Complex Connective Tissue Connective Tissue Diseases Data Degenerative Disorder Deposition Development Differentiation and Growth Event Extracellular Matrix Functional disorder Funding Gene Targeting Genes Genetic Glycoproteins Goals Human Impairment Individual Inherited Injury Kidney Failure Knowledge Lead Ligands Maintenance Metabolic Modeling Molecular Mus Muscle Mutation Organ Organism Peripheral Nerves Physiological Physiology Play Process Property Proteins Proteoglycan Protocols documentation Publishing Research Research Personnel Role Screening procedure Severities Signal Transduction Signaling Molecule Skin Specific qualifier value Staging Structure Testing Tissue Differentiation Tissues Translating Work base cell behavior clinically relevant human disease improved interstitial cell muscle degeneration polarized cell programs repaired research study scaffold

Accounting Adipocytes Adult Architecture Basement membrane Basic Science Behavior Binding Biochemical Biochemical Genetics Biological Biomedical Research Brain hemorrhage Bulla Cardiovascular system Cell Differentiation process Cells Clinical Clinical Management Collagen Complex Connective Tissue Connective Tissue Diseases Data Degenerative Disorder Deposition Development Differentiation and Growth Event Extracellular Matrix Functional disorder Funding Gene Targeting Genes Genetic Glycoproteins Goals Human Impairment Individual Inherited Injury Kidney Failure Knowledge Lead Ligands Maintenance Metabolic Modeling Molecular Mus Muscle Mutation Organ Organism Peripheral Nerves Physiological Physiology Play Process Property Proteins Proteoglycan Protocols documentation Publishing Research Research Personnel Role Screening procedure Severities Signal Transduction Signaling Molecule Skin Specific qualifier value Staging Structure Testing Tissue Differentiation Tissues Translating Work base cell behavior clinically relevant human disease improved interstitial cell muscle degeneration polarized cell programs repaired research study scaffold

展开

项目摘要

DESCRIPTION (provided by applicant): We seek to elucidate how collagen molecules participate in the assembly of higher order tissue structure and implicitly, how collagen dysfunctions contribute to the genesis and progression of connective tissue disorders. Collagens are the most abundant and diverse components of the connective tissue and thus, the major structural determinants of organ formation and function. Stage and tissue-specific interactions among collagens, other matrix components, surrounding cells and signaling molecules are responsible for the variety of forms and functions of the developing and mature connective tissue. In spite of much progress, there is still a significant gap in our understanding of the mechanisms that translate the structural and cellular interactions of collagen molecules into the physiological properties of connective tissues. The lack of this basic science information in turn hampers our ability to model effective new therapies for a variety of human diseases in which organ function is severely or irreversibly impaired. Based on past discoveries and exciting new data, we hypothesize that timely deposition of collagen XIX in selected basement membrane zones (BMZ) specifies their organization and instructs tissue differentiation. BMZ are morphologically defined entities that consist of BM scaffolds interposed between the cells and interstitial matrices. BMZ play both structural and instructive role in tissue formation, maintenance and remodeling. Mutations in BMZ-associated collagens result in clinical manifestations as diverse as skin blistering, cardiovascular dysfunctions, ocular degeneration, kidney failure, hemorrhagic stroke, and muscle degeneration. In contrast to the cell-BM interface, information about the molecular interconnections between the BM and the underlying stroma is still primitive. Our genetic studies in mice have recently implicated collagen XIX as a potential new component of the molecular network that organizes the architecture of specialized BMZ. They have also suggested that assembly of a collagen XlX-rich matrix promotes cell differentiation. It is the main objective of the present application to fully characterize the role of collagen XIX in organ physiology, as the means to advance knowledge of the mechanisms that specify tissue architectures and functions. We therefore propose to characterize the structural and instructive roles of collagen XIX by studying the structural properties and molecular interactions that contribute to BMZ assembly and function, and tissue differentiation and growth. Clinical relevance: The proposed studies will generate new basic science information that will improve our understanding of the genesis and progression of connective tissue disorders, with potential benefits to the clinical management and therapy of many of these debilitating and often lethal conditions.

描述（由申请人提供）：我们试图阐明胶原分子如何参与高阶组织结构的组装，并隐含地胶原蛋白功能障碍如何有助于结缔组织疾病的起源和进展。胶原蛋白是结缔组织中最丰富，最多样化的组成部分，因此是器官形成和功能的主要结构决定因素。胶原蛋白，其他基质组件，周围细胞和信号分子之间的阶段和组织特异性相互作用负责发育和成熟结缔组织的各种形式和功能。尽管取得了很多进展，但我们对将胶原蛋白分子的结构和细胞相互作用转化为结缔组织的生理特性的机制仍然存在很大的差距。缺乏这种基本科学信息反过来妨碍了我们为各种人类疾病的有效新疗法建模的能力，其中器官功能严重或不可逆转地受损。基于过去的发现和令人兴奋的新数据，我们假设在选定的地下室膜区（BMZ）中及时沉积胶原蛋白XIX指定其组织并指示组织分化。 BMZ是形态定义的实体，由细胞和间质基质之间的BM支架组成。 BMZ在组织形成，维护和重塑中既起着结构性又具有启发性作用。与BMZ相关的胶原蛋白的突变导致临床表现如皮肤起泡，心血管功能障碍，眼变性，肾衰竭，出血性中风和肌肉变性。与细胞-BM界面相反，有关BM和基础基质之间的分子互连的信息仍然是原始的。我们在小鼠中的遗传研究最近将胶原蛋白XIX作为组织专门BMZ架构的分子网络的潜在新组成部分。他们还建议，富含胶原蛋白XLX的基质的组装促进细胞分化。目前应用的主要目标是充分表征胶原蛋白在器官生理学中的作用，作为提高指定组织架构和功能的机制知识的手段。因此，我们建议通过研究有助于BMZ组装和功能以及组织分化和生长的结构特性和分子相互作用来表征胶原蛋白XIX的结构和指导作用。临床相关性：拟议的研究将产生新的基础科学信息，从而提高我们对结缔组织障碍的起源和进展的理解，并为许多这些使人衰弱和经常致命状况的临床管理和治疗带来潜在的益处。