Homeostasis and Repair in the Marfan Aorta

该计划项目的总体目标是贡献新的知识，将导致 马凡综合征未来的治疗方法。拟议的调查将使人们更好地了解 生长因子信号在MFS中的作用以及影响细胞和时间靶向的新知识 未来的疗法。项目3将使用Fbn1突变的主动脉疾病小鼠模型来研究三个 明确的目标。在目标1中，我们将测试是否不适当地隔离了大量潜伏的转化生长因子β 复合体是马凡氏动脉疾病发生和发展的主要机制 综合症。为了测试这种疾病机制，我们产生了一种新的小鼠模型，在这种模型中， 原纤维蛋白-1中介导与潜在的转化生长因子β结合蛋白-1和-4结合的位点已被删除。在……里面 目的2，我们将检验主动脉疾病的主要机制是否发生在平滑肌中层。 以及出生后突变纤维蛋白-1的合成是否足以导致主动脉疾病。至 研究这些假设，我们已经在纤维蛋白-1中产生了一个新的“条件”截断突变 老鼠。拟议的研究将导致关于涉及主动脉的关键细胞过程的新信息 VSMC对突变的纤维蛋白-1的反应。对于ECM在体内对特定基因的局部影响知之甚少。 器官的细胞室，以及当地的细胞外基质环境是否以及如何对细胞 器官内各隔室之间的信号。在Aim 2中提出的研究将剖析当地 突变的ECM环境对VSMC在主动脉病理生理中行为的影响。纤维蛋白-1在主动脉中的作用 虽然动态平衡显然很重要，但人们对它的理解还不够深入。一种可能性是产生的纤维蛋白-1 在发育过程中，在动态平衡期间是必需的。另一种可能性是纤维蛋白-1的合成是 在动态平衡期间是必需的。目标2中的研究将确定出生后是否以及在多大程度上 突变的纤维蛋白-1的表达与主动脉疾病有关。这些研究将更好地定义 有效治疗方案的机会。在目标3中，我们将测试BMP信号是否异常 在小鼠主动脉疾病模型中激活，这种激活何时发生，以及阻断是否异常 BMP信号将预防小鼠模型中的主动脉疾病。建议对这些机制进行投资 将包括主动脉根部的形态和超微结构检查，定量RT-PCR， 免疫化学研究、细胞培养研究和体内治疗试验。

The overall goal of the Program Project is to contribute new knowledge that will lead to the development of future therapies for the Marfan syndrome. Proposed investigations will result in a better understanding of the roles of growth factor signaling in MFS and new knowledge that will impact cellular and temporal targeting of future therapies. Project 3 will use Fbnl mutant mouse models of aortic disease in order to investigate three specific aims. In Aim 1, we will test whether inappropriate sequestration of the large latent TGF beta complex is the major mechanism responsible for the initiation and progression of aortic disease in the Marfan syndrome. In order to test this mechanism of disease, we have generated a new mouse model in which the site in fibrillin-1 that mediates binding to the latent TGF beta binding proteins -1 and -4 has been deleted. In Aim 2, we will test whether the major mechanisms of aortic disease take place in the smooth muscle media of the aorta and whether postnatal synthesis of mutant fibrillin-1 is sufficient to cause aortic disease. To investigate these hypotheses, we have generated a new "conditional" truncating mutation in fibrillin-1 in mice. Proposed investigations will lead to new information on key cellular processes involved in aortic VSMC responses to mutant fibrillin-1. Little is known about the in vivo local effects of ECM on specific cellular compartments of an organ and whether and how the local ECM environment contributes to cellular signaling between compartments in an organ. Studies proposed in Aim 2 will dissect the effects of the local mutant ECM environment on VSMC behavior in aortic pathophysiology. The role of fibrillin-1 during aortic homeostasis, while clearly important, is not well understood. One possibility is that fibrillin-1, produced during development, is required during homeostasis. Another possibility is that fibrillin-1 synthesis is required during homeostasis. Studies in Aim 2 will determine whether and to what extent postnatal expression of mutant fibrillin-1 contributes to aortic disease. These studies will better define the window of opportunity for effective therapeufic protocols. In Aim 3, we will test whether BMP signaling is abnormally activated in mouse models of aortic disease, when this activation occurs, and whether blocking abnormal BMP signaling will prevent aortic disease in mouse models. Proposed invesfigafions of these mechanisms will include morphological and ultrastructural examinations of the aortic root, quantitative RT-PCR, immunochemical studies, cell culture studies, and in vivo therapeutic trials.