Consortium for Translational Research in Marfan Syndrome

描述（由申请人提供）：马凡氏综合征（MPS）是一种常见的结缔组织疾病，由细胞外微纤维的主要结构组分flbrillln-1突变引起。我们最初推测并随后证明，f1 br 111 n-1突变损害细胞外基质（ECM）中潜在TGFB复合物的隔离，对细胞性能产生有害后果。这一开创性的发现使人们认识到，TGFB阻断（特别是通过氯沙坦介导的血管紧张素II受体I活性拮抗作用）是减轻MFS小鼠模型和人类患者全身表现的有效策略。我们的工作还确定了其他致病过程，这些过程代表了治疗MFS的潜在新靶点，也是此次更新申请的重点。下一个资助周期将研究的致病过程包括继发于混杂TGFB信号传导的内皮细胞命运的发育性改变。（项目1），导致组成性TGFB激活的细胞和细胞外事件（项目2），基质诱导的主动脉稳态扰动和修复（项目3），以及血管和骨骼系统中不适当的p38 MAPK活性和不平衡的TGFB和BMP信号传导（项目4）。MFS发病机制的这些不同方面将在也缺乏相关信号传导分子或用特异性效应物的抑制剂治疗的疾病的小鼠模型中进行研究。将通过突变细胞和组织的体外研究补充和扩大以小鼠为基础的分析。与过去一样，我们研究计划的高度整合努力是基于四个项目的独特但重叠的假设，其最终合并将描述初始ECM改变如何转化为MFS中的异常细胞反应。此外，行政核心（核心A）和成像和抗体核心（核心B）的专业服务将继续为我们联盟的研究活动提供关键支持。相关性：MFS代表了单基因疾病的一个独特例子，它使我们了解了组织变性和我们使用基于药物的治疗减轻疾病进展的能力。拟议的研究将通过确定新的治疗生物靶点以及血管和骨骼表现的预后生物标志物（构成MFS的主要死亡率和发病率因素），进一步推进这一知识。

DESCRIPTION (provided by applicant): Marfan syndrome (MPS) is a common connective tissue disorder caused by mutations In flbrillln-1, the major Structural component of extracellular microfibrils. We originally speculated and have subsequently demonstrated that flbrlllln-1 mutations Impair the sequestration of latent TGFB complexes In the extracellular matrix (ECM) with deleterious consequences to cellular performance. This seminal discovery has led to the realization that TGFB blockade (specifically through losartan-mediated antagonism of angiotensin II receptor I activity) is a productive strategy to mitigate systemic manifestations in mouse models of MFS and human patients. Our work has also identified additional disease-causing processes that represent potential new targets for treatment of MFS and that are the focus of this renewal application. The disease-causing processes that will be investigated in the next funding cycle Include developmentally-lmposed changes of endothelial cell fate secondary to promiscuous TGFB signaling (Project 1), cellular and extracellular events leading to constitutive TGFB activation (Project 2), matrix-Induced perturbations of aorta homeostasis and repair (Project 3), and improper p38 MAPK activity and unbalanced TGFB and BMP signaling in the vascular and skeletal systems, respectively (Project 4). These different aspects of MFS pathogenesis will be interrogated in mouse models of the disease that are also deficient In relevant signaling molecules or that are treated with Inhibitors of specific effectors. Mouse-based analyses will be complemented and expanded by in vitro studies of mutant cells and tissues. As In the past, the highly Integrated effort of our research program is based on the unique but overlapping hypotheses of the four projects, whose ultimate amalgamation will delineate how initial ECM alterations are translated into aberrant cellular responses in MFS. Furthermore, the specialized services of the Administrative Core (Core A) and the Imaging and Antibodies Core (Core B) will continue to provide critical support to the research activities of our Consortium. RELEVANCE: MFS represents a unique example of a monogenic disorder that has informed our understanding of tissue degeneration and our ability to mitigate disease progression using a drug-based therapy. The proposed studies will further advance this knowledge by identifying new biological targets for therapy, as well as prognostic biomarkers of vascular and skeletal manifestations, which constitute the major mortality and morbidity factors in MFS.