Protein Kinase D2 Function and Signaling in Angiogenesis

描述（由申请人提供）：血管生成在许多生理过程和各种人类疾病的病理条件中起着至关重要的作用，包括缺血性血管疾病、动脉粥样硬化、肿瘤生长和转移、糖尿病视网膜病变、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。我们最近报道了丝氨酸/苏氨酸蛋白激酶D2 （PKD2）在内皮细胞（EC）增殖、迁移和体外血管生成中起关键作用，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的表达以及促血管生成细胞因子的产生。我们也积累了大量的新证据，表明PKD2对内皮细胞中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表达至关重要。我们的新发现被引用并得到了其他小组最近发表的一篇论文的强烈支持，该论文表明PKD2是体内肿瘤诱导血管生成的关键调节剂。然而，在其他病理或生理条件下，PKD2是否在体内血管生成中起主要作用尚不清楚，PKD2介导的体内血管生成的分子基础仍不清楚。特别是PKD2是否调节巨噬细胞的促血管生成功能尚未被探讨。该R21重新提交方案旨在通过以下两个特定目的来回答这些重要问题：目的1)使用体内Matrigel血管生成试验确定VEGF-A或多种促血管生成生长因子诱导的血管生成中的PKD2功能和信号；目的2)利用小鼠后肢缺血模型研究PKD2在血管生成中的作用及其分子基础。这项重新提交的R21提案将确定PKD2是体内血管生成的一种新的关键调节剂，并将为PKD2介导的血管生成提供新的见解。除了在内皮细胞中的作用外，该提案还将确定PKD2在缺氧和促血管生成生长因子的巨噬细胞促血管生成反应中的新功能。我们预计这些研究将为PKD2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依据。

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. PUBLIC HEALTH RELEVANCE: This resubmission R21 proposal is designed to test the hypothesis that PKD2 may play a crucial role in angiogenesis under in vivo pathological and physiological conditions and to uncover the molecular basis of PKD2-mediated angiogenesis, which may provide a novel therapeutic target for pro- or anti-angiogenesis therapies.