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有机体发育和功能的毁灭性影响仍然是一个巨大的挑战。我们最近使用MARFAN综合征小鼠模型（MFS）的研究增加了利用新型生物学靶标进行MFS治疗的可能性。正是该计划项目的范围是进一步探索这种可能性并提高我们对微纤维病理生理学的理解，并将这些信息转化为MFS中的生产临床应用的想法。 Project1的重点是研究主动脉夹层的疗法发生，这是MFS死亡率的主要原因。具体而言，我们建议表征分子机制和细胞因子，使升主动脉的原纤维蛋白1缺陷壁易于结构塌陷。我们的基本假设是，MFS中的Fibrillin-1突变引起了复杂的致病序列，其中包括组织完整性的丧失，失调的细胞活性以及扰动的生长因子信号传导。拟议的研究将对使用最先进的技术忠实地复制MF的临床谱的基因工程小鼠模型进行。将追求三个目标。第一个目标采用DNA微阵列和细胞培养实验来鉴定信息分子和细胞事件，导致动脉瘤形成和进展的MF小鼠模型中。第二个目标利用了原纤维蛋白-1和原纤维素-2无效等位基因的遗传组合，以阐明细胞外微纤维对动脉形态发生和稳态的全部贡献。第三目的是创建一种新的突变小鼠菌株，其中纤维蛋白-1无法再结合LTBP1，以确定潜在TGFBETA的基质隔离与发育中主动脉中的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的其他组件相关。最重要的是，对项目1的调查将有助于指导基于药物的基于药物的治疗方法的剖析动脉瘤。