GENETICS OF EXTRACELLULAR MATRIX IN HEALTH AND DISEASE

健康和疾病中细胞外基质的遗传学

• 批准号: 8690202
• 负责人: ZSOLT URBAN
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690202
• 关键词: Address; Adult; Age; Aneurysm; Arteriosclerosis; Binding; Binding Proteins; Biochemical; Biogenesis; Biological; Blood Vessels; Bronchopulmonary Dysplasia; Candidate Disease Gene; Cardiovascular system; Cells; Complex; Connective Tissue; Cutis Laxa; Data; Degenerative Disorder; Deterioration; Development; Disease; Elastic Fiber; Elastic Tissue; Elastin; Embryo; Environment; Extracellular Matrix; Extracellular Space; Fibrillin Microfibrils; Functional disorder; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Programming; Genitourinary system; Genotype; Germ-Line Mutation; Health; Human; Human Development; Laboratories; Lesion; Lung; Mediating; Modeling; Molecular; Molecular Genetics; Mutation; Mutation Spectra; Natural regeneration; Nature; Organism; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Physiology; Process; Proton-Translocating ATPases; Pulmonary Emphysema; Role; Signal Transduction; Syndrome; System; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Zebrafish; age related; base; cohort; disease-causing mutation; fibulin; fibulin-4; gastrointestinal; gene discovery; gene interaction; in vitro Model; knock-down; novel; repaired; research study; small molecule; tissue regeneration; treatment strategy

DESCRIPTION (provided by applicant): The long-range objectives of these studies are to elucidate the functions of the elastic extracellular matrix in human development and physiology, to uncover the molecular mechanisms of disease caused by elastic fiber (EF) dysfunction and to develop novel treatment strategies for these diseases. Several lines of recent evidence highlight the complexity of EF assembly. Cell biological and biochemical studies illustrate the dynamic, hierarchical and cell mediated nature of EF biogenesis. However, key molecular determinants of this process have remained elusive. Molecular genetic studies of patients with vascular anomalies, emphysema and cutis laxa show that multiple genes are required for distinct steps of the EF formation. These studies identified mutations in the genes for elastin, fibulin-4, fibulin-5 and the a2 subunit v- type H+ATPase, highlighting the existence of a network of molecules required for elastogenesis. New preliminary data from our studies now suggest that a downstream effect of different cutis laxa mutations includes dysregulation of transforming growth factor beta (TGFb) signaling. Based on these results we hypothesize that cutis laxa is caused by the disruption of EF biogenesis at multiple levels leading to both structural disruption of elastic fibers and by altered storage and release of TGFb in the extracellular matrix. To address these hypotheses we propose (1) to investigate the genetic program of human EF formation by identifying disease-causing mutations in patients with cutis laxa, emphysema and vascular anomalies. In addition to mutational profiling of recently discovered genes, we will use candidate gene analysis to identify novel genes for these disorders. In aim 2, we will use in vitro models of EF assembly to identify the sequence of molecular interactions between extracellular matrix molecules impacted by cutis laxa mutations. We will also test if EF dysfunction leads to inappropriate TGFb release by destabilizing the large latent complex of TGFb. In aim 3, we intend to dissect the role of fibulin-4 and related molecules in early vascular patterning and subsequent blood vessel maturation using zebrafish as a model. We will use genetics and small molecule drugs to identify the contribution of EF dysfunction and altered TGFb signaling to developmental lesions.

描述(申请人提供)：这些研究的长期目标是阐明弹性细胞外基质在人类发育和生理中的功能，揭示由弹性纤维(EF)功能障碍引起的疾病的分子机制，并为这些疾病开发新的治疗策略。最近的几行证据强调了EF组装的复杂性。细胞生物学和生化研究阐明了EF生物发生的动态性、层次性和细胞介导性。然而，这一过程的关键分子决定因素仍然难以捉摸。对血管畸形、肺气肿和皮肤松弛患者的分子遗传学研究表明，EF形成的不同步骤需要多个基因。这些研究确定了弹性蛋白、纤维蛋白-4、纤维蛋白-5和a2亚单位v型H+ATPase基因的突变，突显了弹性形成所需的分子网络的存在。我们研究的新的初步数据现在表明，不同皮肤松弛突变的下游影响包括转化生长因子β(TGFb)信号的失调。根据这些结果，我们推测皮肤松弛是由于EF生物发生在多个水平上的中断导致了弹性纤维的结构破坏以及TGFb在细胞外基质中的储存和释放的改变。为了解决这些假设，我们建议(1)通过鉴定皮肤松弛、肺气肿和血管异常患者的致病突变来研究人类EF形成的遗传程序。除了最近发现的基因突变图谱外，我们还将使用候选基因分析来识别这些疾病的新基因。在目标2中，我们将使用EF组装的体外模型来确定受皮肤松弛突变影响的细胞外基质分子之间的分子相互作用序列。我们还将测试EF功能障碍是否通过破坏TGFb的大潜伏复合体的稳定性而导致TGFb的不适当释放。在目标3中，我们打算以斑马鱼为模型，剖析纤毛蛋白-4及其相关分子在早期血管构型和随后的血管成熟中的作用。我们将使用遗传学和小分子药物来确定EF功能障碍和改变的TGFb信号在发育损害中的作用。