Mouse Models for Systems Therapeutics Degenerative Diseases

用于系统治疗退行性疾病的小鼠模型

• 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
• 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

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.

项目摘要 胸主动脉瘤（TAA）是以进行性扩张为特征的危及生命的病理 与平滑肌细胞功能障碍和破坏性细胞外基质重塑相关， 导致血管壁撕裂和破裂。目前的TAA管理依赖于常规的早期发现 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 作为一种无偏的组织水平策略，以确定具有重新用途的组合治疗 能够有效靶向小鼠中TAA相关信号通路的药物， 进行性重度马凡氏综合征（MFS）。选择这种TAA的遗传模型是因为 蛋白质（血管紧张素-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， 内皮细胞机械转导，以及血管紧张素II和TGFβ信号转导。我们的建议被组织成 两个具体的目标，结合联合收割机的实验和计算方法，以阐明致病 在MFS小鼠中，多个信号通路和细胞类型在MFS-1缺陷型胰岛中的作用（目的 预测和验证靶向疾病相关信号的组合药物治疗， 穿过不同的壁隔室（目标2）。我们的系统治疗策略有望改变 MFS从一种需要手术干预的致命动脉疾病到一种慢性疾病， 进行医学管理。