Microfibrils in Vascular Morphogenesis and Disease

开发有效的治疗方法来抵消细胞外基质缺乏对生物体发育和功能的破坏性影响仍然是一个艰巨的挑战。我们最近的研究使用小鼠模型的马凡氏综合征（MFS）提出了可能性，利用新的生物靶点的MFS治疗。这正是该计划项目的范围，进一步探索这种可能性，并推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的生产性临床应用。主动脉夹层是MFS的主要死亡原因，项目1的重点是对主动脉夹层发病机制的研究。具体而言，我们建议的分子机制和细胞因子，易患的升主动脉壁结构性塌陷的napkin-1缺陷。我们的基本假设是，MFS中的Escherin-1突变导致复杂的致病序列，包括组织完整性丧失、细胞活性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了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确定负责我们的MFS小鼠模型中动脉瘤形成和进展的信息分子和细胞事件。第二个目的是利用基因的组合，numerin-1和numerin-2无效等位基因，以阐明所有范围的贡献的细胞外微纤维动脉形态发生和稳态。第三个目的提出创建一种新的突变小鼠品系，其中，LtGF-I不再能够结合LTBP 1，以确定在发育和成熟主动脉中潜伏TGF β的基质隔离和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PO 1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夹层动脉瘤的合理药物治疗的发展。

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.