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

• 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
• 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

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（申请人提供）：向缺血组织提供血流的新侧支血管的发育是一个极其复杂的过程，其是由于几种不同的机制而发生的，所述机制包括新血管从现有血管结构发芽，骨髓来源的内皮前体细胞迁移到缺血部位，炎性细胞的募集，以及血管平滑肌细胞的内皮通道（现有的和新形成的）的动脉化。虽然已经了解了很多关于在这些过程中的生长因子的参与，由其他因素，如炎症蛋白介导的适应性血管生长的精确的分子机制，是非常复杂的，需要进一步调查。通过了解驱动侧支血管形成的潜在机制，我们可以开发新的治疗方法来增加阻塞性动脉疾病患者的功能性侧支血管生长，手术基本上是唯一可用的治疗方法。我们已经证明，骨桥蛋白（OPN），炎症细胞因子和基质细胞蛋白，是不可或缺的侧支血管生长的形成，其表达显着上调，响应缺血。然而，最近变得明显的是，人类表达三种OPN同种型（a、B和c），其在各种疾病环境中差异上调并且可能具有不同的功能。目前还不清楚这三种OPN亚型如何影响心血管疾病中的细胞迁移和侧支血管形成。因此，该职业发展提案旨在通过使用新的和翻译的方法将这些OPN亚型递送至缺血组织来定义人OPN亚型在侧支形成过程中的功能差异。我们的初步数据强烈支持，人类骨桥蛋白亚型差异调节侧支血管形成，平滑肌细胞迁移和细胞信号。因此，我们假设人OPN亚型通过对动脉化所必需的炎性细胞和血管平滑肌细胞迁移的不同作用，对侧支形成表现出不同的作用。本申请中描述的实验将剖析这三种人OPN同种型如何起作用以调节这些反应。我们建议利用骨桥蛋白缺陷小鼠来确定每种人骨桥蛋白亚型在新血管形成中的具体作用，并将通过研究以下具体目标来检验我们的总体假设：1）确定人OPN同种型在体内侧支血管形成中的作用，2）研究人OPN同种型对血管平滑肌细胞迁移的不同作用，和3）确定人OPN同种型介导差异细胞迁移的机制。