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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：
8386273
负责人：
DENIZ TOKSOZ-EXLEY
金额：
$ 23.85万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8386273
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. PUBLIC HEALTH RELEVANCE: Vascular smooth muscle remodeling underlies several pulmonary diseases. This proposal will study the molecular mechanisms of vascular smooth muscle remodeling by generating and characterizing a novel genetic animal model in mice that is engineered to have a Rho kinase gene "knock-out" only in smooth muscle tissue.

描述（由申请人提供）：血管平滑肌重塑在几种肺部疾病的发展中起关键作用，包括肺动脉高压，这是一种致命的疾病，最终导致心力衰竭。因此，有必要在这一领域进行研究。本提案的目的是通过产生和表征一种新的遗传小鼠模型来研究体内重塑过程的分子基础。这些模型对于确定关键基因产物的特定作用和随后的疾病发病机制中的信号通路是必要的。Rho GT3及其主要作用或Rho激酶（ROCK）介导许多血管平滑肌细胞反应，如收缩性和生长，其也涉及重塑过程。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的变化。此外，ROCK与啮齿类动物实验诱导的肺动脉高压的发展有关。然而，许多体内数据是基于使用药理学ROCK抑制剂（Y27632，法舒地尔），这是不具体的;因此，在体内的作用，ROCK在血管平滑肌重塑仍然是独立确定。有两个ROCK基因，我们的假设是，ROCK 1在血管平滑肌重塑和肺动脉高压的发展中发挥了独特的作用，但这还没有在遗传动物模型中进行研究。在此基础上，Specific Aim 1将产生独特的血管平滑肌靶向ROCK 1基因敲除（KO）小鼠品系。特定目标2将表征靶向KO菌株的表型。Aim 2将包括基线和应激反应（如缺氧）的体内研究，以及ROCK 1 KO菌株培养的血管平滑肌细胞的细胞和信号传导反应研究。总体而言，目标将产生和表征一种新的遗传ROCK动物模型，并在体内测试ROCK 1有助于重塑和肺动脉高压疾病的假设。公共卫生相关性：血管平滑肌重塑是几种肺部疾病的基础。该提案将通过在小鼠中产生和表征一种新的遗传动物模型来研究血管平滑肌重塑的分子机制，该模型被设计为仅在平滑肌组织中具有Rho激酶基因“敲除”。