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Homeostasis and Repair in the Marfan Aorta

马凡主动脉的稳态和修复

基本信息

批准号：
8122264
负责人：
LYNN Y SAKAI
金额：
$ 29.14万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8122264
关键词：
Accounting Address Affect Age-Months Angiotensin II Angiotensin II Type 1 Receptor Blockers Aorta Aortic Diseases Appearance Architecture Area Binding Binding Proteins Binding Sites Blood Vessels Caring Cartoons Cell Culture Techniques Cell physiology Child Collaborations Complement Complex Data Defect Development Dilatation - action Disease Environment Epithelial Equilibrium Event Extracellular Matrix FBN1 Fetal Development Functional disorder Funding Future Goals Growth Factor Homeostasis Individual Investigation Knowledge Lead Losartan MAPK14 gene Marfan Syndrome Mediating Mesenchymal Microfibrils Modeling Molecular Morphology Mus Mutant Strains Mice Mutation Organ Outcome Pathogenesis Pathway interactions Phenotype Plant Roots Protocols documentation Reagent Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Site Skeletal Development Smooth Muscle Smooth Muscle Myocytes Specific qualifier value TGFB1 gene Testing Therapeutic Therapy Clinical Trials Time Transforming Growth Factor beta Work base biological adaptation to stress bone morphogenetic protein 7 cell behavior cellular targeting design in vivo interest latent TGF-beta binding protein mouse model mutant mutant mouse model novel postnatal prenatal prevent programs receptor expression repaired response skeletal disorder

项目摘要

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.

该计划项目的总体目标是贡献新知识，从而促进发展马凡综合征的未来治疗方法。拟议的调查将有助于更好地了解生长因子信号传导在 MFS 中的作用以及将影响细胞和时间靶向的新知识未来的治疗方法。项目 3 将使用主动脉疾病的 Fbnl 突变小鼠模型来研究三个具体目标。在目标 1 中，我们将测试大的潜在 TGF beta 是否被不当隔离复合体是马凡主动脉疾病发生和进展的主要机制综合症。为了测试这种疾病机制，我们建立了一种新的小鼠模型，其中 fibrillin-1 中介导与潜在 TGF beta 结合蛋白 -1 和 -4 结合的位点已被删除。在目标2，我们将测试主动脉疾病的主要机制是否发生在平滑肌中层主动脉的变化以及突变原纤维蛋白-1 的出生后合成是否足以引起主动脉疾病。到研究这些假设，我们在 fibrillin-1 中产生了一个新的“条件”截短突变老鼠。拟议的研究将带来有关主动脉关键细胞过程的新信息 VSMC 对突变原纤蛋白-1 的反应。关于 ECM 对特定细胞的体内局部影响知之甚少。器官的细胞区室以及局部 ECM 环境是否以及如何影响细胞器官内隔室之间的信号传导。目标 2 中提出的研究将剖析当地环境的影响突变 ECM 环境对主动脉病理生理学中 VSMC 行为的影响。 fibrillin-1 在主动脉粥样硬化过程中的作用体内平衡虽然显然很重要，但人们还没有很好地理解。一种可能性是 fibrillin-1，产生在发育过程中，是体内平衡所必需的。另一种可能性是 fibrillin-1 的合成是体内平衡期间需要。目标 2 的研究将确定是否以及在多大程度上产后突变 fibrillin-1 的表达会导致主动脉疾病。这些研究将更好地定义制定有效治疗方案的机会。在目标3中，我们将测试BMP信号是否异常在主动脉疾病小鼠模型中激活，何时激活，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。对这些机制的拟议研究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。