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（由适用提供）：心血管疾病对人类健康造成了巨大的燃烧，我们的长期目标是减轻对许多疾病中心的血管平滑肌细胞（VSMC）的过量积累。正常动脉的TUNICA培养基由VSMC和弹性薄片的替代圆周层组成。各种动脉疾病，包括动脉粥样硬化，再狭窄，肺动脉高压和上主动脉瓣狭窄（SVAS）受到缺陷的弹性薄片以及高肌关闭的困扰。 SVA是一种毁灭性的人类疾病，其特征是占据大动脉的VSMC燃烧增加，是由弹性蛋白基因ELN中的杂合无效突变引起的。同样，弹性蛋白突变小鼠会发展出大动脉（例如主动脉）的高肌关闭和狭窄。主要血管手术是目前唯一的治疗对于SVA，由于没有有效的药理选择。开发有效疗法血管疾病的主要障碍是对过量VSMC的细胞来源的不良理解。确实，没有先前的研究可以追溯弹性蛋白突变体中任何细胞群体的谱系。另外，弹性蛋白突变体中主动脉高度肌化的基于的分子和细胞机制尚未很好地定义。我们的初步研究表明，整联蛋白表达和整联蛋白信号在弹性蛋白突变主动脉中有牢固地更新，并且降低水平或活性会减轻过量的肌肉化。此外，降低了编码ITGB3基因的剂量，扩大了ELN（ - / - ）幼崽的生存能力，这是任何遗传或药物干预的前所未有的。减少SVA中动脉高肌化的潜在有吸引力的策略正在减弱表达的增加。尽管在表达调节方面知之甚少，但在VSMC和GAX过表达中表达生长特异性同源（GAX）转录因子可降低水平，增殖和迁移。我们假设在弹性蛋白突变体中，GAX下调会诱导整联蛋白的表达，从而导致主动脉平滑肌肉，从而导致异常的VSMC方向，增殖和迁移，从而导致主动脉狭窄。该建议利用从鼠主动脉和人类SVAS主动脉组织和细胞中分离出的转基因突变小鼠的研究，以三个特定目的在三个特定目的中检验这一假设：1）在弹性蛋白突变主动脉中，确定过量VSMC的细胞源； 2）在弹性蛋白不足的小鼠中，鼠VSMC和人类SVAS衍生的平滑肌细胞，阐明整联蛋白诱导的多余主动脉肌肉的分子和细胞机制； 3）阐明了GAX在介导弹性蛋白突变体中增强整合素表达和高肌关闭的作用。综上所述，我们提出的研究将描述弹性蛋白缺乏症，整合素和主动脉高度骨化之间的联系的基础机制，从而为开发针对SVA和其他血管增生性疾病的新型治疗策略提供了具体步骤。