Pathological arterial muscularization and the role of integrins

病理性动脉肌化和整合素的作用

基本信息

批准号：
8969702
负责人：
Daniel Greif
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-11-17 至 2018-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8969702
关键词：
Actins Adhesions Aorta Aortic Valve Stenosis Arterial Disorder Arterial Medias Arteries Atherosclerosis Attenuated Blood Vessels Blood flow Caliber Cardiovascular Diseases Cell Differentiation process Cell Proliferation Cells Cytoskeleton Disease Distal Down-Regulation Elastin Embryo Endothelial Cells Extracellular Matrix Gene Dosage Genes Genetic Goals Growth Health Homeobox Human Injury Integrin beta3 Integrins Intervention Knockout Mice Link Longevity Lung Maps Mediating Mitogens Modeling Molecular Mus Mutant Strains Mice Operative Surgical Procedures Pathogenesis Pathology Pericytes Phenotype Plague Population Pulmonary Hypertension Regulation Role Series Signal Transduction Smooth Muscle Smooth Muscle Myocytes Source Stenosis Stimulus Sum Supravalvular aortic stenosis Testing Tissues Transgenic Organisms Tunica Media Up-Regulation Vascular Diseases Vascular Smooth Muscle Work arteriole cell motility combat dosage effective therapy human disease in vivo induced pluripotent stem cell injured loss of function mutation migration mouse model mutant novel novel therapeutics null mutation overexpression postnatal prevent pup receptor response restenosis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular diseases exert a massive burden on human health, and our long term objective is to attenuate the excessive accumulation of vascular smooth muscle cells (VSMCs) that is central to many of these diseases. The tunica media of the normal artery is composed of alternating circumferential layers of VSMCs and elastic lamellae. Diverse arterial disorders, including atherosclerosis, restenosis, pulmonary hypertension and supravalvular aortic stenosis (SVAS) are plagued by defective elastic lamellae as well as hypermuscularization. SVAS, a devastating human disease characterized by an increased VSMC burden that occludes large arteries, is caused by heterozygous null mutations in the elastin gene ELN. Similarly, elastin mutant mice develop hypermuscularization and stenosis of large arteries, such as the aorta. Major vascular surgery is the only current treatment for SVAS as no effective pharmacological options are available. A major obstacle to developing effective therapies for vascular disorders is the poor understanding of the cellular source(s) of excess VSMCs; indeed no prior studies have traced the lineage of any cell populations in elastin mutants. In addition, the molecular and cellular mechanisms underlying aortic hypermuscularization in elastin mutants are not well defined. Our initial studies indicate that integrin �expression and integrin signaling is robustly upregulated in the elastin mutant aorta and that reduction of �levels or activity attenuates the excessive muscularization. Furthermore, reduction of the dosage of the gene encoding � Itgb3, extends the viability of Eln(-/-) pups which is unprecedented for any genetic or pharmacological intervention. A potentially attractive strategy for reducing arterial hypermuscularization in SVAS is attenuating the increased �expression. Although little is known regarding regulation of �expression, the growth arrest-specific homeobox (Gax) transcription factor is expressed in VSMCs and Gax overexpression reduces �levels, proliferation and migration. We hypothesize that in elastin mutants, Gax downregulation induces integrin �expression in pre-existing aortic smooth muscle resulting in aberrant VSMC orientation, proliferation and migration and thus aortic stenosis. This proposal utilizes studies of transgenic mutant mice, VSMCs isolated from the murine aorta and human SVAS aortic tissue and cells to test this hypothesis in three specific aims: 1) in the elastin mutant aorta, identify the cellular source(s) of excessive VSMCs; 2) in elastin deficient mice, murine VSMCs and human SVAS-derived smooth muscle cells, elucidate the molecular and cellular mechanisms underlying integrin �induced excess aortic muscularization; and 3) elucidate the role of Gax in mediating enhanced integrin �expression and hypermuscularization in elastin mutants. Taken together, our proposed studies will delineate mechanisms underlying the identified link between elastin deficiency, integrin �and aortic hypermuscularization and thereby provide concrete steps towards developing novel therapeutic strategies for SVAS and other vasculoproliferative diseases.

描述（由申请人提供）：心血管疾病给人类健康带来巨大负担，我们的长期目标是减少血管平滑肌细胞（VSMC）的过度积累，血管平滑肌细胞是许多此类疾病的核心组成部分。 VSMC 和弹性板层的交替周向疾病，包括动脉粥样硬化、再狭窄、肺动脉高压和瓣膜上病变。主动脉瓣狭窄 (SVAS) 受到弹性板层缺陷和肌肉过度化的困扰，SVAS 是一种毁灭性的人类疾病，其特征是血管平滑肌细胞负担增加，导致大动脉闭塞，是由弹性蛋白基因 ELN 的杂合无效突变引起的。出现大动脉过度肌肉化和狭窄，例如主动脉，大血管手术是目前唯一的治疗方法。对于 SVAS 来说，由于没有有效的药物选择，开发治疗血管疾病的有效疗法的一个主要障碍是对过量 VSMC 的细胞来源了解甚少；事实上，之前没有研究追踪过弹性蛋白突变体中任何细胞群的谱系。此外，弹性蛋白突变体主动脉肌化过度的分子和细胞机制尚未明确，我们的初步研究表明，整合素表达和整合素信号传导在弹性蛋白突变体中显着上调。此外，减少编码 Itgb3 的基因剂量，可以延长 Eln(-/-) 幼崽的生存能力，这对于任何遗传或药物干预来说都是前所未有的。减少 SVAS 中动脉过度肌肉化的一个潜在有吸引力的策略是减弱有关生长停滞特异性同源框 (Gax) 表达的增加，尽管对表达的调节知之甚少。我们发现，在弹性蛋白突变体中，Gax 下调会诱导现有主动脉平滑肌中整合素的表达，导致 VSMC 方向、增殖和迁移异常，从而导致主动脉瓣狭窄。该提案利用对转基因突变小鼠、从小鼠主动脉分离的 VSMC 以及人类 SVAS 主动脉组织和细胞的研究来验证这一假设。具体目标：1) 在弹性蛋白突变主动脉中，确定过量 VSMC 的细胞来源；2) 在弹性蛋白缺陷小鼠、鼠 VSMC 和人 SVAS 衍生平滑肌细胞中，阐明整合素诱导的分子和细胞机制过度主动脉肌化；3) 阐明 Gax 在介导弹性蛋白突变体中整合素表达增强和过度肌化中的作用。总而言之，我们提出的研究将描绘弹性蛋白缺乏、整合素和主动脉过度肌肉化之间已确定的联系的潜在机制，从而为开发 SVAS 和其他血管增殖性疾病的新治疗策略提供具体步骤。