Consortium for Translational Research in Marfan Syndrome

马凡氏综合症转化研究联盟

基本信息

批准号：
8776626
负责人：
Francesco B Ramirez
金额：
$ 21.24万
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：
2013
资助国家：
美国
起止时间：
2013-12-05 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776626
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

项目摘要

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）：Marfan综合征（MPS）是由Flbrillln-1突变引起的常见结缔组织障碍，Flbrillln-1是细胞外微纤维的主要结构成分。我们最初猜测并随后证明了flbrlllllln-1突变会损害细胞外基质（ECM）中潜在TGFB复合物的隔离，对细胞性能产生了有害后果。这种开创性的发现导致人们意识到，TGFB阻滞（特别是通过Losartan介导的血管紧张素II受体I活性的拮抗作用）是一种富有成效的策略，可以减轻MFS和人类患者小鼠模型中的系统性表现。我们的工作还确定了其他引起疾病的过程，这些过程代表了治疗MFS的潜在新目标，这是该更新应用的重点。 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分别在血管和骨骼系统中的BMP信号传导（项目4）。 MFS发病机理的这些不同方面将在疾病的小鼠模型中询问，这些模型也缺乏相关信号分子或用特定效应子抑制剂处理的疾病。基于小鼠的分析将通过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综合努力基于这四个项目的独特但重叠的假设，它们的最终合并将描述如何将初始ECM变化转化为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）的专业服务将继续为我们财团的研究活动提供关键的支持。相关性：MFS代表了一种单基因疾病的独特例子，该疾病已经为我们对组织变性的理解以及使用基于药物的治疗来减轻疾病进展的能力。拟议的研究将通过确定治疗的新生物学靶标，以及血管和骨骼表现的预后生物标志物，进一步推进这一知识，这构成了MFS中的主要死亡率和发病因素。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The fibrillin microfibril scaffold: A niche for growth factors and mechanosensation?

DOI：
10.1016/j.matbio.2015.05.002
发表时间：
2015-09-01
期刊：
MATRIX BIOLOGY
影响因子：
6.9
作者：
Sengle, Gerhard;Sakai, Lynn V.
通讯作者：
Sakai, Lynn V.

FBN1: The disease-causing gene for Marfan syndrome and other genetic disorders.

DOI：
10.1016/j.gene.2016.07.033
发表时间：
2016-10-10
期刊：
Gene
影响因子：
3.5
作者：
Sakai LY;Keene DR;Renard M;De Backer J
通讯作者：
De Backer J

LTBPs, more than just an escort service.

DOI：
10.1002/jcb.23385
发表时间：
2012-02
期刊：
JOURNAL OF CELLULAR BIOCHEMISTRY
影响因子：
4
作者：
Todorovic, Vesna;Rifkin, Daniel B.
通讯作者：
Rifkin, Daniel B.

Fibrillin microfibrils in bone physiology.

DOI：
10.1016/j.matbio.2015.09.004
发表时间：
2016-05
期刊：
Matrix biology : journal of the International Society for Matrix Biology
影响因子：
0
作者：
Smaldone S;Ramirez F
通讯作者：
Ramirez F

Function of latent TGFβ binding protein 4 and fibulin 5 in elastogenesis and lung development.

DOI：
10.1002/jcp.24704
发表时间：
2015-01
期刊：
JOURNAL OF CELLULAR PHYSIOLOGY
影响因子：
5.6
作者：
Dabovic, Branka;Robertson, Ian B.;Zilberberg, Lior;Vassallo, Melinda;Davis, Elaine C.;Rifkin, Daniel B.
通讯作者：
Rifkin, Daniel B.