Microfibrils in Vascular Morphogenesis and Disease

微原纤维在血管形态发生和疾病中的作用

基本信息

批准号：
7460909
负责人：
Francesco B Ramirez
金额：
$ 31.63万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460909
关键词：
Adult Affect Alleles Aneurysm Aorta Arts Basic Science Behavior Therapy Binding Binding Sites Biochemical Biological Blood Vessels Cells Clinical Complex Cultured Cells Cytokine Activation DNA Microarray Chip DNA Microarray format Dependence Development Disease Dissecting Aneurysm Dissecting aortic aneurysm Dissection Embryo Embryonic Development Event Extracellular Matrix FBN1 Face Functional disorder Genetic Genetically Engineered Mouse Goals Growth Factor Homeostasis Investigation Knockout Mice Link Lung Marfan Syndrome Microfibrils Molecular Molecular Profiling Morbidity - disease rate Morphogenesis Mus Mutant Strains Mice Mutation Organ Organism Pathway interactions Performance Perinatal Pharmaceutical Preparations Phenotype Play Predisposing Factor Protocols documentation Range Role Signal Transduction Smooth Muscle Myocytes Stress Technology Testing Thoracic Aortic Aneurysm Tissues Transforming Growth Factor beta Translating Ursidae Family Work ascending aorta base body system clinical application design extracellular fibrillin fibrillin-2 hemodynamics heritable connective tissue disorder innovation mortality mouse model mutant novel postnatal programs research study response

项目摘要

Development of effective therapies to counteract the devastating effects of extracellular matrix deficiencies on organismal development and function remains a formidable challenge. Our recent studies using mouse models of Marfan Syndrome (MFS) have raised the possibility of utilizing novel biological targets for MFS therapy. It is precisely the scope of this Program Project to explore further this possibility and advance our understanding of microfibril pathophysiology, with the idea of translating this information into productive clinical applications in MFS. Project1 focuses on the study of the etiopathogenesis of aortic dissection, the leading cause of mortality in the MFS. Specifically, we propose to characterize the molecular mechanisms and cellular factors that predispose the fibrillin-1-deficient wall of the ascending aorta to structural collapse. Our underlying hypothesis is that fibrillin-1 mutations in MFS cause a complex pathogenetic sequence that includes loss of tissue integrity, dysregulated cellular activities, and perturbed growth factor signaling. The proposed studies will be performed on genetically engineered mouse models that faithfully replicate the clinical spectrum of MFS using state-of-the-art technologies. Three aims will be pursued. The first aim employs DNA microarray and cell culture experiments to identify information molecular and cellular events responsible for aneurysm formation and progression in our mouse models of MFS. The second aim exploits genetic combinations of fibrillin-1 and fibrillin-2 null alleles to elucidate the full range of contributions of the extracellular microfibrils to arterial morphogenesis and homeostasis. The third aim proposes to create a new strain of mutant mice in which fibrillin-1 can no longer bind LTBP1 in order to determine the functional relationship between matrix sequestration of latent TGFbeta and growth factor signaling in the developing and mature aorta. These aims are conceptually and experimentally inter-related with the other components of the PO1. Most importantly, the investigations of Project 1 will be instrumental in guiding the development of rational drug-based treatments of dissecting aneurysm in MFS.

开发有效的疗法来抵消细胞外基质缺陷对生物体发育和功能的破坏性影响仍然是一项艰巨的挑战。我们最近使用马凡氏综合症 (MFS) 小鼠模型进行的研究提出了利用新的生物靶标进行 MFS 治疗的可能性。该计划项目的范围正是进一步探索这种可能性并增进我们对微纤维病理生理学的理解，并将这些信息转化为 MFS 中富有成效的临床应用。项目 1 重点研究主动脉夹层的发病机制，主动脉夹层是 MFS 死亡的主要原因。具体来说，我们建议描述导致升主动脉原纤维蛋白-1缺陷的壁易于结构塌陷的分子机制和细胞因素。我们的基本假设是，MFS 中的 fibrillin-1 突变会导致复杂的发病序列，包括组织完整性丧失、细胞活动失调和生长因子信号传导紊乱。拟议的研究将在基因工程小鼠模型上进行，这些模型使用最先进的技术忠实地复制 MFS 的临床谱。将追求三个目标。第一个目标是利用 DNA 微阵列和细胞培养实验来识别与 MFS 小鼠模型中动脉瘤形成和进展有关的信息分子和细胞事件。第二个目标利用 fibrillin-1 和 fibrillin-2 无效等位基因的遗传组合来阐明细胞外微原纤维对动脉形态发生和稳态的全方位贡献。第三个目标是创建一种新的突变小鼠品系，其中 fibrillin-1 不再能结合 LTBP1，以确定潜在 TGFbeta 的基质隔离与发育和成熟主动脉中生长因子信号传导之间的功能关系。这些目标在概念上和实验上与 PO1 的其他组成部分相互关联。最重要的是，项目 1 的研究将有助于指导 MFS 夹层动脉瘤合理药物治疗的开发。