Protein Kinase D2 Function and Signaling in Angiogenesis

蛋白激酶 D2 在血管生成中的功能和信号转导

• 批准号: 8298983
• 负责人: HUA TANG
• 金额: $ 17.63万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8298983
• 关键词: Age related macular degeneration; Atherosclerosis; Biological Assay; Cell Proliferation; Cell membrane; Cells; Culture Media; Diabetic Retinopathy; Endothelial Cells; Enzymes; Fibroblast Growth Factor Receptor 1; Growth Factor; Growth Factor Receptors; Hypoxia; In Vitro; Ischemia; Lead; Ligands; Limb structure; Mediating; Minor; Modeling; Molecular; Neoplasm Metastasis; Physiological; Physiological Processes; Play; Production; Protein Isoforms; Publications; RNA Splicing; Reporting; Rheumatoid Arthritis; Role; Serine; Signal Transduction; Testing; Therapeutic Intervention; Threonine; Vascular Diseases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; angiogenesis; antiangiogenesis therapy; base; cytokine; design; human disease; in vivo; insight; macrophage; matrigel; migration; mouse model; mutant; new therapeutic target; novel; particle; protein kinase D2; receptor; response; small hairpin RNA; therapeutic angiogenesis; tumor; tumor growth

DESCRIPTION (provided by applicant): Angiogenesis plays a crucial role in numerous physiological processes and in a wide variety of pathological conditions of human diseases, including ischemic vascular diseases, atherosclerosis, tumor growth and metastasis, diabetic retinopathy, age-related macular degeneration, and rheumatoid arthritis. Hence identification of key angiogenesis regulators may lead to develop more specific and efficacious new therapies for treating angiogenesis-associated human diseases. We have recently reported that the serine/threonine protein kinase D2 (PKD2) plays a pivotal role in endothelial cell (EC) proliferation, migration, and in vitro angiogenesis in part through modulation of the expression of vascular endothelial growth factor (VEGF) receptor-2 and fibroblast growth factor receptor-1 and the production of proangiogenic cytokines. We have also accumulated substantial new evidence indicating that PKD2 is essential for the expression of numerous other important proangiogenic growth factor receptors, receptor ligands, and plasma membrane enzymes in ECs. Our novel findings are cited and strongly supported by a recent publication from other group showing that PKD2 is a crucial regulator of tumor-induced angiogenesis in vivo. However, it is not known whether PKD2 plays a major role in angiogenesis in vivo under other pathological or physiological conditions, and the molecular basis of PKD2-mediated angiogenesis in vivo is still not clear. Especially, whether PKD2 regulates the proangiogenic functions of macrophages has not been explored. This resubmission R21 proposal is designed to answer these important questions with the following two Specific Aims: Aim 1) To determine PKD2 function and signaling in angiogenesis induced by VEGF-A or multiple proangiogenic growth factors using in vivo Matrigel angiogenesis assay; Aim 2) To determine the role and molecular basis of PKD2 in angiogenesis using a mouse model of hind-limb ischemia. This resubmission R21 proposal will identify PKD2 as a novel and key regulator of angiogenesis in vivo and will provide new insights into the PKD2-mediated angiogenesis. In addition to its role in ECs, this proposal will identify a novel function of PKD2 in macrophage proangiogenic responses by hypoxia and proangiogenic growth factors. We anticipate that these studies will provide a strong rationale for PKD2 as a novel drugable target for therapeutic intervention in angiogenesis- related human diseases.

描述（由申请人提供）：血管生成在许多生理过程和人类疾病的多种病理状况中起关键作用，所述人类疾病包括缺血性血管疾病、动脉粥样硬化、肿瘤生长和转移、糖尿病性视网膜病、年龄相关性黄斑变性和类风湿性关节炎。因此，确定关键的血管生成调节因子可能会导致开发更具体和有效的新疗法来治疗血管生成相关的人类疾病。我们最近报道，丝氨酸/苏氨酸蛋白激酶D2（PKD 2）在内皮细胞（EC）的增殖，迁移和体外血管生成中起着关键作用，部分通过调节血管内皮生长因子（VEGF）受体-2和成纤维细胞生长因子受体-1的表达和促血管生成细胞因子的产生。我们还积累了大量的新证据表明，PKD 2是必不可少的许多其他重要的促血管生成生长因子受体，受体配体，和质膜酶的EC中的表达。我们的新发现被引用，并强烈支持最近出版的其他小组表明，PKD 2是一个重要的调节肿瘤诱导的血管生成在体内。然而，目前尚不清楚PKD 2是否在其他病理或生理条件下在体内血管生成中起主要作用，并且PKD 2介导的体内血管生成的分子基础仍然不清楚。特别是，PKD 2是否调节巨噬细胞的促血管生成功能尚未探索。本次重新提交的R21提案旨在回答这些重要问题，具有以下两个具体目的：目的1）使用体内Matrigel血管生成测定法确定PKD 2在VEGF-A或多种促血管生成生长因子诱导的血管生成中的功能和信号传导;目的2）使用小鼠后肢缺血模型确定PKD 2在血管生成中的作用和分子基础。这一重新提交的R21提案将确定PKD 2作为体内血管生成的一种新的关键调节因子，并将为PKD 2介导的血管生成提供新的见解。除了其在EC中的作用之外，该提案还将确定PKD 2在缺氧和促血管生成生长因子引起的巨噬细胞促血管生成反应中的新功能。我们预期这些研究将为PKD 2作为血管生成相关人类疾病治疗干预的新型药物靶点提供强有力的理论基础。