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Targeted Rho kinase-1 KO Mouse Model for Vascular Smooth Muscle Remodeling

用于血管平滑肌重塑的靶向 Rho 激酶 1 KO 小鼠模型

基本信息

批准号：
8534274
负责人：
DENIZ TOKSOZ-EXLEY
金额：
$ 18.92万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8534274
关键词：
Actomyosin Animal Model Animals Area Blood Vessels Cardiac Cell Cycle Progression Cells Code Cultured Cells Data Development Disease Engineering Exhibits Functional disorder Generations Genes Genetic Genetic Models Genetic Transcription Growth Heart failure Hypertension Hypoxia In Vitro Knock-out Knockout Mice Link Lung Lung diseases Mediating Modeling Molecular Mouse Strains Mus Muscle Tonus Myosin ATPase Pathogenesis Pathway interactions Phenotype Play Process Progressive Disease Protein Isoforms Proteins Pulmonary Hypertension ROCK1 gene Reporting Research Rho-associated kinase Rodent Role Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Stress Takeda brand of pioglitazone hydrochloride Testing Vascular Smooth Muscle Vascular remodeling base fasudil in vivo in vivo Model inhibitor/antagonist mouse model novel pressure promoter protective effect pulmonary arterial hypertension response rho rho GTP-Binding Proteins vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Vascular smooth muscle remodeling plays a key role in the development of several pulmonary diseases, including pulmonary hypertension, a fatal disease that culminates in heart failure. Thus, there is a need for research in this area. The objective of this proposal is to study the molecular basis of the remodeling process in vivo by generating and characterizing a novel genetic mouse model. Such models are necessary to define the particular role of key gene products and ensuing signaling pathways in disease pathogenesis. The Rho GTPase and its primary effect or, Rho kinase (ROCK), mediate many vascular smooth muscle cell responses such as contractility and growth which are also implicated in the remodeling process. Data in cultured cells have shown that Rho/ROCK participate in pulmonary vascular smooth muscle cell proliferation and acto-myosin cytoskeletal changes. Moreover, ROCK is implicated in the development of experimentally-induced pulmonary hypertension in rodents. However, much of the in vivo data is based on the use of pharmacological ROCK inhibitors (Y27632, fasudil) that are not specific; therefore the in vivo role of ROCK in vascular smooth muscle remodeling remains to be independently determined. There are two ROCK genes, and our hypothesis is that ROCK1plays a distinct role in vascular smooth muscle remodeling and in pulmonary hypertension development, but this has not been studied in a genetic animal model. On this basis, Specific Aim 1 will generate a unique vascular smooth muscle-targeted ROCK1 gene knock-out (KO) mouse strain. Specific Aim 2 will characterize the phenotype of the targeted KO strain. Aim2 will include in vivo studies at baseline and in response to stress such as hypoxia, and studies of cellular and signaling responses of cultured vascular smooth muscle cells derived from the ROCK1KO strain. Overall, the Aims will generate and characterize a novel genetic ROCK animal model, and test the hypothesis in vivo that ROCK1 contributes to remodeling and pulmonary hypertensive disease.

描述（由申请人提供）：血管平滑肌重塑在多种肺部疾病的发展中起着关键作用，包括肺动脉高压，这是一种最终导致心力衰竭的致命疾病。因此，有必要进行这方面的研究。该提案的目的是通过生成和表征新型遗传小鼠模型来研究体内重塑过程的分子基础。这些模型对于定义关键基因产物和随后的信号通路在疾病发病机制中的特殊作用是必要的。 Rho GTP 酶及其主要作用或 Rho 激酶 (ROCK) 介导许多血管平滑肌细胞反应，例如收缩性和生长，这些反应也与重塑过程有关。培养细胞的数据表明，Rho/ROCK 参与肺血管平滑肌细胞增殖和肌动球蛋白细胞骨架变化。此外，ROCK 与啮齿动物实验诱发的肺动脉高压的发生有关。然而，许多体内数据都是基于使用药理学 ROCK 抑制剂（Y27632、fasudil），这些抑制剂并不具有特异性；因此，ROCK 在血管平滑肌重塑中的体内作用仍有待独立确定。 ROCK 基因有两个，我们的假设是 ROCK1 在血管平滑肌重塑和肺动脉高压发展中发挥着独特的作用，但这尚未在遗传动物模型中进行过研究。在此基础上，Specific Aim 1将产生独特的血管平滑肌靶向ROCK1基因敲除（KO）小鼠品系。具体目标 2 将表征目标 KO 菌株的表型。 Aim2 将包括基线和缺氧等应激反应的体内研究，以及来自 ROCK1KO 菌株的培养血管平滑肌细胞的细胞和信号反应研究。总体而言，该目标将生成并表征一种新型遗传 ROCK 动物模型，并在体内测试 ROCK1 有助于重塑和肺动脉高压疾病的假设。