Osteopontin and Collateral Vessel Growth

骨桥蛋白和侧支血管生长

• 批准号: 8296360
• 负责人: William Robert Taylor
• 金额: $ 34.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-18 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8296360
• 关键词: Adult; Anatomy; Apoptosis; Atherosclerosis; Blood Vessels; Blood capillaries; Blood flow; Bone Marrow; Bone Tissue; Bone remodeling; Breast; Cell Survival; Cells; Complex; Data; Dependence; Development; Endothelial Cells; Exercise stress test; Experimental Neoplasms; Fibroblast Growth Factor 2; Generations; Goals; Growth; Growth Factor; Health; Histology; Image; Implant; In Vitro; Inflammatory; Inflammatory Response; Integrins; Ischemia; Lasers; Learning; Ligands; Limb structure; Lymphocyte; Malignant neoplasm of lung; Mediating; Metastatic Neoplasm to the Bone; Modeling; Molecular; Mus; Names; Neoplasm Metastasis; Osteogenesis; Oxidative Stress; Patients; Perfusion; Phosphoproteins; Physiological; Play; Process; Proteins; Reactive Oxygen Species; Regulation; Role; Secondary to; Site; Smooth Muscle Myocytes; Source; Stomach; Structure; Supporting Cell; T-Lymphocyte; Therapeutic; Tissues; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascularization; Work; Wound Healing; angiogenesis; base; bone; capillary; cell motility; cell type; defined contribution; in vivo; insight; macrophage; malignant breast neoplasm; malignant stomach neoplasm; mature animal; migration; neovascularization; neuroblastoma cell; osteopontin; postnatal; precursor cell; prevent; soft tissue; tumor growth

DESCRIPTION (provided by applicant): The development of new collateral blood vessels to provide blood flow to ischemic tissue is an extremely complex process that occurs as a result of several distinct processes 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 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 such as VEGF and bFGF the precise molecular mechanisms underlying adaptive vascular growth are extremely complex and remain incompletely understood. The secreted phosphoprotein osteopontin, well known as a modulator of bone remodeling, is being considered in the present study for its potential role in reparative angiogenesis. Circumstantial evidence supporting a possible role for osteopontin in vascular growth comes from several sources including the observations that osteopontin supports cell migration, prevents apoptosis of endothelial cells and is growth promoting for smooth muscle cells. In addition, osteopontin is a ligand for 1v21-3 integrins which are known to be important in cell survival and neovascularization. These data are supported by the observations that wound healing (a process that may involve angiogenesis) is impaired in osteopontin deficient (OPN-/-) mice. Furthermore, recent studies employing transfected murine neuroblastoma cells secreting high levels of osteopontin show that osteopontin enhances local angiogenesis and promotes tumor growth. It has also been shown that expression of osteopontin correlates with progression of gastric, breast and lung cancers. Conversely, osteopontin deficiency has been shown to reduce experimental tumor cell metastasis to bone and soft tissues and to reduce resorption of implanted ectopic bone secondary to reduced vascularization. We have recently shown that osteopontin positively modulates vascular inflammatory processes which suggest an additional important mechanism through which osteopontin can enhance neovascularization in the adult. Based on these circumstantial data, we hypothesize that osteopontin plays a pivotal role in postnatal vascular growth. We propose to make use of osteopontin deficient mice to define the functional role of osteopontin in new vessel formation and to further define the contributions of inflammatory responses to this process. PUBLIC HEALTH RELEVANCE: The development of new blood vessels in the adult is an important mechanism through which the adult can compensate for blockages in blood vessels that are caused by atherosclerosis. This work will study osteopontin, an important protein that is thought to be very important in regulating this process. The ultimate goal is to develop better therapeutic approaches to treating patients with atherosclerosis.

描述（由申请人提供）：开发新的附带血管以向缺血组织提供血液流动是一个极其复杂的过程，由于几个不同的过程，包括从现有血管结构中发芽的新血管，骨髓的迁移。 - 衍生的内皮前体细胞对缺血部位，炎症细胞的募集以及具有血管平滑肌细胞的内皮通道（现有和新形成）的动脉化。尽管有关生长因子（例如VEGF和BFGF）的参与已经有很多了解，但适应性血管生长的确切分子机制非常复杂，并且尚未完全理解。在本研究中，正在考虑其在修复性血管生成中的潜在作用，因此在本研究中考虑了分泌的磷蛋白骨蛋白骨phist蛋白，众所周知。支持骨桥蛋白在血管生长中可能作用的间接证据来自多种来源，包括骨桥蛋白支持细胞迁移，防止内皮细胞的凋亡，并促进平滑肌细胞的生长。另外，骨桥蛋白是1V21-3整联蛋白的配体，已知在细胞存活和新血管形成中很重要。这些数据得到了观察到的，即伤口愈合（可能涉及血管生成的过程）在骨桥蛋白缺乏（OPN - / - ）小鼠中受损。此外，最近采用转染的鼠神经母细胞瘤细胞分泌高水平骨桥蛋白的研究表明，骨桥蛋白可增强局部血管生成并促进肿瘤的生长。还已经表明，骨桥蛋白的表达与胃，乳腺癌和肺癌的进展相关。相反，骨桥蛋白缺乏症已被证明可减少实验性肿瘤细胞向骨和软组织的转移，并减少继发于减少血管形成的植入异位骨的吸收。我们最近表明，骨桥蛋白正阳性调节血管炎症过程，这表明了骨桥蛋白可以增强成年人的新血管形成的其他重要机制。基于这些间接数据，我们假设骨桥蛋白在产后血管生长中起关键作用。我们建议利用骨桥蛋白缺乏小鼠来定义骨桥蛋白在新血管形成中的功能作用，并进一步定义炎症反应对这一过程的贡献。公共卫生相关性：成人新血管的发展是一个重要的机制，成年人可以通过该机制来补偿由动脉粥样硬化引起的血管的阻塞。这项工作将研究骨桥，这是一种重要的蛋白质，被认为在调节这一过程中非常重要。最终目标是开发更好的治疗方法来治疗动脉粥样硬化患者。