The Role of Human Osteopontin Isoforms in Collateral Formation

人骨桥蛋白亚型在侧支形成中的作用

基本信息

批准号：
8700885
负责人：
Alicia N Lyle
金额：
$ 9.84万
依托单位：
EMORY 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：
2014-04-04 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700885
关键词：
Accounting Adhesions Affinity Aging Alginates Anatomy Arterial Occlusive Diseases Arteries Biological Assay Blood Vessels Blood capillaries Blood flow Bone Marrow Bypass CD44 gene Cardiovascular Diseases Cell Proliferation Cell Survival Cells Cessation of life Complementary DNA Complex Cytokine Signaling Data Development Disease Embryonic Development Encapsulated Endothelial Cells Exercise stress test Exhibits Exons Goals Growth Growth Factor Histology Human Image In Vitro Infiltration Inflammation Inflammatory Integrins Investigation Ischemia Lead Learning Length Life Limb structure Link Mediating Mesenchymal Stem Cells Molecular Mus Myocardial Infarction Operative Surgical Procedures Pathology Patients Perfusion Peripheral arterial disease Physiological Physiological Processes Play Post-Translational Protein Processing Process Protein Isoforms Proteins Reperfusion Therapy Rodent Role Signal Transduction Site Smooth Muscle Myocytes Stem cells Stroke Structure Subfamily lentivirinae Testing Therapeutic Tissues Tube United States Vascular Endothelial Cell Woman Work angiogenesis arteriole capillary career development cell motility cell type cellular imaging cytokine design immunocytochemistry in vivo interest macrophage men migration mortality novel novel strategies novel therapeutic intervention osteopontin overexpression precursor cell receptor research study response translational approach vascular smooth muscle cell migration vasculogenesis

项目摘要

DESCRIPTION (provided by applicant): The development of new collateral blood vessels to provide blood flow to ischemic tissues is an extremely complex process that occurs as a result of several distinct mechanisms including sprouting of new blood vessels from existing vascular structures, migration of bone marrow-derived endothelial precursor cells to sites of ischemia, recruitment of inflammatory cells, and the arterialization of endothelial channels (both existing and newly formed) with vascular smooth muscle cells. While much has been learned about the involvement of growth factors in these processes, the precise molecular mechanisms underlying adaptive vascular growth mediated by other factors, such as inflammatory proteins, are extremely complex and require further investigation. By understanding the underlying mechanisms that drive collateral vessel formation, we can develop new therapeutic approaches to increase functional collateral growth in patients with obstructive arterial disease for which surgery is essentially the only available treatment. We have demonstrated that osteopontin (OPN), an inflammatory cytokine and matricellular protein, is integral to the formation of collateral vessel growth and its expression is significantly upregulated in response to ischemia. However, it has recently become evident that humans express three OPN isoforms (a, b, and c), which are differentially upregulated in various disease settings and may have different functions. There is currently nothing known about how these three OPN isoforms function to influence cell migration and collateral vessel formation in cardiovascular disease. Therefore, this career development proposal was designed to define the functional differences of the human OPN isoforms in the collateral formation process by using a novel and translational approach to deliver these OPN isoforms to ischemic tissues. Our preliminary data strongly support that human osteopontin isoforms differentially regulate collateral vessel formation, smooth muscle cell migration, and cell signaling. We therefore hypothesize that human OPN isoforms exhibit differential effects on collateral formation through divergent effects on the migration of inflammatory cells and vascular smooth muscle cells, necessary for arterialization. The experiments described in this application will dissect how these three human OPN isoforms function to modulate these responses. We propose to make use of osteopontin deficient mice to define the specific role of each human osteopontin isoform in new vessel formation and will test our overall hypothesis by investigating the following specific aims: 1) Define the role of human OPN isoforms on collateral vessel formation in vivo, 2) Investigate the differential effects of human OPN isoforms on vascular smooth muscle cell migration, and 3) Determine the mechanism by which human OPN isoforms mediate differential cell migration.

描述（由申请人提供）：开发新的附带血管向缺血组织提供血液流动是一个极其复杂的过程，这是由于几种不同的机制而发生的，包括从现有血管结构中萌芽的新血管，骨髓衍生的内皮细胞迁移到骨髓衍生的前体细胞，以及脑部疾病的疾病，以及疾病的新疾病，是疾病的新血管，以及繁殖的新血管，是疾病的新血管，以及疾病的新血管（又是新血管与血管平滑肌细胞形成）。尽管有关生长因子在这些过程中的参与的知识已经很多，但由其他因素（例如炎症蛋白）介导的自适应血管生长的确切分子机制非常复杂，需要进一步研究。通过了解驱动附带血管形成的潜在机制，我们可以开发新的治疗方法，以增加阻塞性动脉疾病患者的功能性侧支生长，而手术本质上是唯一可用的治疗方法。我们已经证明，骨桥蛋白（OPN）是一种炎性细胞因子和母细胞蛋白，是副血管生长的形成不可或缺的，其表达在响应缺血的响应中显着上调。但是，最近显而易见的是，人类表达三种OPN同工型（A，B和C），它们在各种疾病环境中被差异上调，并且可能具有不同的功能。目前，这三种OPN同工型如何影响细胞迁移和心血管疾病中的副血管形成尚不了解。因此，该职业发展建议旨在通过使用新颖的转化方法将这些OPN同工型传递到缺血性组织中，以定义侧支形成过程中人类OPN同工型的功能差异。我们的初步数据强烈支持人骨桥蛋白同工型差异地调节侧支血管形成，平滑肌细胞迁移和细胞信号传导。因此，我们假设人类OPN同工型通过对炎性细胞和血管平滑肌细胞的迁移而对附带形成表现出不同的影响，这是动脉化所必需的。本应用中描述的实验将剖析这三个人类OPN同工型如何调节这些响应。 We propose to make use of osteopontin deficient mice to define the specific role of each human osteopontin isoform in new vessel formation and will test our overall hypothesis by investigating the following specific aims: 1) Define the role of human OPN isoforms on collateral vessel formation in vivo, 2) Investigate the differential effects of human OPN isoforms on vascular smooth muscle cell migration, and 3) Determine the mechanism人OPN同工型介导差异细胞迁移。