Consortium for Translational Research in Marfan Syndrome

描述(由申请人提供)： 马凡综合征(MFS)是一种常见的全身性结缔组织疾病，由细胞外微纤维的主要成分原纤维-1的突变引起。尽管进展导致受影响个体的平均寿命延长，但多器官系统的表现仍然是导致MFS发病率和死亡率的重要因素。该计划的长期目标是将基质生物学的基础研究发现转化为有效的治疗策略，用于治疗MFS患者和相关的结缔组织疾病。将通过实施综合和多学科方法来实现这一值得称道的目标，该方法综合了这一领域和相关研究领域的四个主要实验室的科学兴趣和实验专长。我们的目标是牢固地基于我们之前建立的范例，即纤维蛋白-1缺乏会导致TGFbeta超家族信号分子的失调。我们的工作模型是，富含纤维蛋白的微纤维直接通过特定的分子相互作用调节信号事件，并通过关键的细胞基质相互作用间接调节信号事件。这个模型将在MFS的基因工程小鼠模型中进行研究，使用生化、细胞、超微结构、分子、组织学、生理和表型参数。该计划的主要研究主题包括：(A)导致动脉瘤进展的细胞事件，(B)纤维蛋白-1控制TGFbeta/BMP信号的结构要求，(C)导致纤维蛋白-1缺乏的基质中细胞因子失调的机制，以及(D)其他TGFbeta超家族成员参与MFS的发病机制和体内拮抗，以探索潜在的治疗策略。这些主题将由四个项目进行，这些项目在概念上和实验上相互结合和相互依存。研究计划的整体进展有赖于成像和抗体核心的专门服务以及行政核心的行政和文书支持。

DESCRIPTION (provided by applicant): The Marfan syndrome (MFS) is a common, systemic disorder of connective tissue caused by mutations in fibrillin-1, the major constituent of extracellular microfibrils. In spite of advances leading to increased average life span for affected individuals, manifestations in multiple organ systems remain significant contributors to morbidity and mortality in the MFS. The long-term goal of this program is to translate basic research discoveries in matrix biology into productive therapeutic strategies for the management of individuals with MFS and related disorders of connective tissue. This meritorious goal will be pursued through the implementation of a comprehensive and multidisciplinary approach that integrates the scientific interest and experimental expertise of four leading laboratories in this and related research fields. The goal is solidly based on our previously established paradigm that fibrillin-1 deficiency results in dysregulation of TGFbeta super family signaling molecules. Our working model is that fibrillin-rich microfibrils regulate signaling events directly through specific molecular interactions, and indirectly through critical cell matrix interactions. This model will be investigated in genetically engineered mouse models of MFS using biochemical, cellular, ultrastructural, molecular, histological, physiological and phenotypic parameters. The main research themes of the Program include the study of (a) cellular events underlying aneurysm progression, (b) structural requirements for fibrillin-1 control of TGFbeta/BMP signaling, (c) mechanisms responsible for cytokine dysregulation in fibrillin-1 deficient matrices, and (d) involvement of other TGFbeta super family members in MFS pathogenesis and in vivo antagonism to explore potential therapeutic strategies. These themes will be pursued by four projects that are conceptually and experimentally integrated with and dependent upon one another. Overall progress of the research program relies on the specialized services of the Imaging and Antibodies Core and the administrative and clerical support of the Administrative Core.