Consortium for Translational Research in Marfan Syndrome

马凡氏综合症转化研究联盟

• 批准号: 8724113
• 负责人: Francesco B Ramirez
• 金额: $ 15.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-08 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8724113
• 关键词: Achievement; Angiotensin II Receptor; Antibodies; Aorta; Basic Science; Biological; Blood Vessels; Cells; Complement; Complex; Connective Tissue; Connective Tissue Diseases; Disease; Disease Progression; Endothelial Cells; Event; Extracellular Matrix; Funding; Goals; Homeostasis; Human; Image; In Vitro; Knowledge; Laboratories; Losartan; MAP Kinase Gene; MAPK14 gene; Marfan Syndrome; Mediating; Microfibrils; Morbidity - disease rate; Mus; Mutation; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Process; Prognostic Marker; Program Research Project Grants; Research; Research Activity; Secondary to; Seminal; Services; Signal Transduction; Signaling Molecule; Skeletal system; TGFB1 gene; Tissues; Translating; Translational Research; Vascular System; Work; base; extracellular; inhibitor/antagonist; mortality; mouse model; mutant; novel therapeutics; programs; repaired; response; skeletal; skills

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.

描述（由申请人提供）：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 flbrlllln-1 突变会损害细胞外基质 (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症状的有效策略。我们的工作还确定了其他致病过程，这些过程代表了 MFS 治疗的潜在新目标，也是本次更新申请的重点。将在下一个资助周期中研究的致病过程包括继发于混杂的 TGFB 信号传导（项目 1）、导致组成性 TGFB 激活的细胞和细胞外事件（项目 2）、基质诱导的内皮细胞命运的发育性变化主动脉稳态和修复的扰动（项目 3），以及血管和血管中不正确的 p38 MAPK 活性以及不平衡的 TGFB 和 BMP 信号传导分别是骨骼系统（项目 4）。 MFS发病机制的这些不同方面将在该疾病的小鼠模型中进行研究，这些模型也缺乏相关信号分子或用特定效应物的抑制剂治疗。基于小鼠的分析将通过突变细胞和组织的体外研究得到补充和扩展。与过去一样，我们研究计划的高度整合工作基于四个项目独特但重叠的假设，其最终合并将描述最初的 ECM 改变如何转化为 MFS 中的异常细胞反应。此外，管理核心（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，它让我们了解了组织变性以及我们使用药物疗法减缓疾病进展的能力。拟议的研究将通过确定新的治疗生物学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因素）来进一步推进这一知识。