Homeostasis and Repair in the Marfan Aorta

该计划项目的总体目标是贡献新的知识，这将导致发展 马凡氏综合征的未来疗法拟议的调查将有助于更好地了解 生长因子信号在MFS中的作用，以及将影响MFS细胞和时间靶向的新知识。 未来的治疗项目3将使用主动脉疾病的Fbnl突变小鼠模型，以研究三种 具体目标。在目标1中，我们将测试是否不适当的隔离大的潜在TGF β， 复合体是马凡氏体主动脉疾病发生和发展的主要机制 综合征为了测试这种疾病的机制，我们已经产生了一种新的小鼠模型， 介导与潜在TGF β结合蛋白-1和-4结合的β-内酰胺酶蛋白-1中的位点已被删除。在 目的2，我们将检测主动脉疾病的主要机制是否发生在平滑肌中膜 以及出生后合成的突变体Bcl 1是否足以引起主动脉疾病。到 通过研究这些假设，我们在大肠杆菌中产生了一种新的“条件性”截短突变， 小鼠拟议的调查将导致新的信息的关键细胞过程参与主动脉 VSMC对突变型β-淀粉样蛋白-1的反应。关于ECM在体内对特定的细胞的局部作用知之甚少。 器官的细胞区室以及局部ECM环境是否以及如何有助于细胞的生长。 在器官中的隔室之间传递信号。目标2中提出的研究将剖析当地 突变ECM环境对主动脉病理生理学中VSMC行为的影响。血管紧张素-1在主动脉粥样硬化形成中的作用 内稳态虽然很重要，但还没有得到很好的理解。一种可能性是， 在发育过程中，是体内平衡所必需的。另一种可能性是， 在体内平衡过程中所需要的。目标2中的研究将确定产后是否以及在多大程度上 突变型β-内酰胺酶-1的表达导致主动脉疾病。这些研究将更好地确定 有效治疗方案的机会。在目标3中，我们将测试BMP信号传导是否异常 在小鼠主动脉疾病模型中激活，当这种激活发生时，以及阻断是否异常 BMP信号传导将预防小鼠模型中的主动脉疾病。对这些机制的拟议调查 将包括主动脉根部的形态学和超微结构检查，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.