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 胸动脉瘤（TAA）是威胁生命的病理，其特征是进行性词典 与平滑肌细胞功能障碍和破坏性的细胞外基质重塑有关 导致容器壁的撕裂和破裂。 TAA的当前管理依赖于常规的早期检测 通过手术程序进行成像和促进性修复。该建议的主要目标是使用系统 治疗是一种公正的组织水平策略 可以轻松靶向与TAA相关的信号通路的药物早期发作的小鼠 逐渐严重的Marfan综合征（MFS）。选择TAA的遗传模型是因为突变 蛋白质（Fibrillin-1）调节动脉功能和稳态的几个关键方面，包括组织完整性， 内皮细胞机械转导，血管紧张素II和TGFβ信号传导。我们的建议被组织到 结合了实验和计算方法以阐明致病性的两个特定目的 MFS小鼠的原纤维蛋白1缺陷主动脉中多种信号通路和细胞类型的贡献（AIM 1）;并验证并验证靶向与疾病相关信号的组合药物治疗和 在不同的墙壁隔间（AIM 2）。我们的系统治疗策略有望改变 来自致命的动脉疾病的MF，需要手术干预到慢性病 在医学上进行管理。