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Marfan Aortic Embryologic Origin Influences Aneurysm Formation

马凡主动脉胚胎起源影响动脉瘤的形成

基本信息

批准号：
10551326
负责人：
Michael Peter Fischbein
金额：
$ 65.46万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551326
关键词：
Affect Age Androgens Aneurysm Aorta Aortic Aneurysm Automobile Driving Basic Science Biological Process Biomechanics Cause of Death Cell Lineage Cell model Cells Chemosensitization Clinical Collagen Connective Tissue Diseases Deposition Development Disease Dissection Embryo Extracellular Matrix FBN1 Functional disorder Funding Future Genes Goals Growth Guanosine Triphosphate Phosphohydrolases Health Heart Human In Vitro Inherited Learning Life Expectancy Marfan Syndrome Matrix Metalloproteinases Mediating Medical MicroRNAs Modeling Molecular Mus Muscle Contraction Mutation NADP Neural Crest Operative Surgical Procedures Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Play Pluripotent Stem Cells Population Production Property Proteolysis Proteomics Reactive Oxygen Species Regimen Reporting Research Role Rupture Severity of illness Signal Transduction Smooth Muscle Myocytes Transforming Growth Factor beta Transgenic Mice Translating Translations Vascular Smooth Muscle Work cell motility design drug development drug discovery experimental study in vivo innovation male mannose receptor mechanical properties mouse model new therapeutic target novel paracrine pharmacologic prophylactic response scaffold single-cell RNA sequencing stem cell differentiation stem cell model targeted treatment transcriptomics treatment strategy

项目摘要

PROJECT SUMMARY Marfan syndrome (MFS), caused by mutations in the fibrillin-1 gene, is the most common inherited connective tissue disorder. Patients typically develop aortic root aneurysms with ensuing aortic dissection and rupture remaining the leading cause of death. Without prophylactic surgery, life-expectancy is reduced to age 40 years. Novel targeted drug therapies have been absent, likely due to limitations in mechanistic understanding. Thus, there is an urgent need to dissect the pathway(s) involved in MFS aortic wall extracellular matrix (ECM) breakdown resulting in aneurysm formation. We hypothesize that distinct embryonic origins of SMCs populating the aortic root contribute to aortic root-specific aneurysm pathophysiology. In the recent funding period, we created and characterized induced-pluripotent stem cells (iPSCs) from MFS patients and differentiated them into SMCs from each embryologic origin. We learned that the microRNA, miR-29b and related downstream genes were dependent on SMC embryologic origin. After applying high-throughput proteomics, we also discovered that iPSC-derived SMCs from MFS patients express distinct, lineage-specific proteomic profiles affecting critical biologic processes including ECM synthesis/degeneration and SMC contraction/motility. Utilizing single-cell RNA sequencing, we identified a distinct, disease-specific SMC cluster that develops transcriptomic alterations regionally in both murine models and human aortic root aneurysms. In complimentary MFS Fbn1C1041G/+ mouse in vivo studies, we discovered several regional upstream TGF-β-dependent triggers that ultimately increase matrix metalloproteinase-mediated ECM remodeling, including: (a) Ras (GTPase) signaling; (b) NADPH activation leading to reactive oxygen species production; and (c) androgen potentiation of TGF-β signaling in male mice. Drug blockade of each discovered pathway reduced aneurysm formation. In this renewal application, we rigorously expand our research progress by proposing several innovative experiments to study the relative contributions of SMC lineages to regional ECM remodeling, investigate the upstream triggers and pathologic role of modulated SMCs during aneurysm formation, and advance the translation of disease-specific iPSC modeling for novel pathway discovery. Specific Aim 1 seeks whether interactions between MFS SHF- and neural crest-SMCs induce synthetic SMC phenotype and ECM remodeling. We investigate the novel role of reduced SHF-SMC mannose receptor 2 (MRC2) on ECM composition, proteolysis and SMC contractile function. We will also elucidate the effect of ECM biomechanical properties on lineage-specific SMC responses, including SMC transcriptomic modulation and single cell mechanical properties. Specific Aim 2 strives to determine the effects of modulated SMC populations on ECM remodeling in vitro using our innovative MFS decellularized matrix scaffolds. Novel lineage-tracing transgenic mouse models will be utilized to identify modulated SMC embryologic origin and role in aneurysm progression in vivo.

项目总结