Mouse Models for Systems Therapeutics Degenerative Diseases

用于系统治疗退行性疾病的小鼠模型

基本信息

批准号：
9244242
负责人：
Srinivas Ravi V Iyengar
金额：
$ 52.2万
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：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9244242
关键词：
Angiotensin II Angiotensin II Receptor Angiotensins Aorta Aortic Aneurysm Automobile Driving Biological Biological Models Blood Vessels Cessation of life Chronic Clinical Communication Complement Connective Tissue Diseases Cytoskeleton Data Degenerative Disorder Development Disease Disease Pathway Disease Progression Dissection Drug Combinations Drug Targeting Drug effect disorder Early Diagnosis Endothelial Cells Experimental Models Extracellular Matrix FBN1 Functional disorder Gene Targeting Genes Genetic Genetic Models Genotype Goals Homeostasis Immunohistochemistry Inflammatory Infiltrate Inherited Knowledge Lead Life Marfan Syndrome Medial Medical Modality Molecular Morbidity - disease rate Mus Mutate Mutation Nature Operative Surgical Procedures Outcome Pathogenicity Pathology Pathway interactions Periodicity Pharmaceutical Preparations Pharmacology Pharmacotherapy Prevention Property Proteins Public Health Regimen Research Risk Rupture Sampling Signal Pathway Signal Transduction Smooth Muscle Myocytes System Therapeutic Thoracic Aortic Aneurysm Tissues Transforming Growth Factor beta Translating Treatment Protocols Validation base cell type combinatorial differential expression early onset experimental study gene product hemodynamics human disease innovation insight intima media loss of function mutation mechanotransduction mortality mouse model novel therapeutics postnatal prophylactic receptor repaired response routine imaging targeted treatment tissue degeneration whole genome

项目摘要

Project summary Thoracic aortic aneurysms (TAA) are life-threatening pathologies characterized by progressive dilation associated with smooth muscle cell dysfunction and destructive extracellular matrix remodeling that ultimately lead to tear and rupture of the vessel wall. Current management of TAA relies on early detection by routine imaging and prophylactic repair by surgical procedures. The main goal of this proposal is to use systems therapeutics as an unbiased tissue-level strategy to identify combinatorial treatments with repurposed drugs that can efficaciously target TAA-related signaling pathways in mice with early onset, progressively severe Marfan syndrome (MFS). This genetic model of TAA was chosen because the mutated protein (fibrillin-1) regulates several key aspects of arterial function and homeostasis, including tissue integrity, endothelial cell mechanotransduction, and angiotensin II and TGFβ signaling. Our proposal is organized into two specific aims that combine experimental and computational approaches to elucidate the pathogenic contributions of multiple signaling pathways and cell types in the fibrillin-1-deficient aortas of MFS mice (Aim 1); and predict and validate combinatorial drug treatments targeting disease-associated signals within and across distinct wall compartments (Aim 2). Our system therapeutics strategy is expected to transform MFS from a deadly arterial disease that requires surgical intervention to a chronic condition that can be managed medically.

项目概要胸主动脉瘤（TAA）是一种危及生命的疾病，其特征是进行性扩张与平滑肌细胞功能障碍和破坏性细胞外基质重塑相关，最终导致导致血管壁撕裂和破裂，目前 TAA 的治疗依赖于常规的早期检测。通过外科手术进行成像和预防性修复该提案的主要目标是使用系统。治疗作为一种公正的组织水平策略，用于识别具有重新用途的组合治疗可以有效靶向早发小鼠 TAA 相关信号通路的药物，选择这种 TAA 基因模型是因为发生了突变。蛋白质 (fibrillin-1) 调节动脉功能和体内平衡的几个关键方面，包括组织完整性、我们的建议分为内皮细胞机械转导、血管紧张素 II 和 TGFβ 信号传导。结合实验和计算方法来阐明致病因素的两个具体目标 MFS 小鼠原纤维蛋白 1 缺陷主动脉中多种信号通路和细胞类型的贡献（Aim 1); 预测和验证针对疾病相关信号的组合药物治疗跨越不同的壁室（目标 2）。 MFS 是一种致命的动脉疾病，需要手术干预，而慢性疾病可以进行医疗管理。