Consortium for Translational Research in Marfan Syndrome

描述(申请人提供)：马凡综合征(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成分flbrillln-1突变引起。我们最初推测并随后证明，flbrlln-1突变损害了潜在的TGFb复合体在细胞外基质(ECM)中的隔离，从而对细胞性能造成有害后果。这一开创性的发现使人们认识到，阻断TGFb(特别是通过氯沙坦介导的血管紧张素II受体I活性的拮抗)是一种有效的策略，可以缓解MFS小鼠模型和人类患者的全身症状。我们的工作还确定了更多的致病过程，这些过程代表了治疗MFS的潜在新靶点，也是此次续签申请的重点。将在下一个资助周期中研究的致病过程包括：继发于TGFb信号混乱的内皮细胞命运的发育性改变(项目1)，导致结构性TGFb激活的细胞和细胞外事件(项目2)，基质诱导的主动脉内稳态和修复的扰动(项目3)，以及血管和骨骼系统中p38MAPK的不正确活性和TGFb和BMP信号的失衡(项目4)。MFS发病机制的这些不同方面将在疾病的小鼠模型中进行询问，这些小鼠也缺乏相关的信号分子，或者使用特定效应物的抑制剂进行治疗。基于老鼠的分析将通过对突变细胞和组织的体外研究来补充和扩展。与过去一样，我们的研究计划的高度整合的努力是基于四个项目独特但重叠的假设，这四个项目的最终融合将描绘出最初的ECM改变如何转化为MFS中异常的细胞反应。此外，行政核心(核心A)和成像和抗体核心(核心B)的专门服务将继续为我们联盟的研究活动提供重要支持。相关性：MFS代表了一个独特的单基因疾病的例子，它使我们了解了组织退化，并了解了我们使用基于药物的治疗来缓解疾病进展的能力。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来进一步促进这一知识，这些生物标志物构成了MFS的主要死亡和发病因素。

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.