Molecular regulation of angiogenesis

血管生成的分子调控

• 批准号: 8877622
• 负责人: ZHENG-GEN JIN
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-16 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8877622
• 关键词: Age related macular degeneration; Antibodies; Apoptosis; Apoptotic; Biological; Biological Process; Blindness; Blood Vessels; Caspase; Cell Proliferation; Cell Survival; Cell physiology; Development; Disease; Endothelial Cells; Endothelium; Event; Family; Genes; Genetic Transcription; Growth Factor; HDAC7 histone deacetylase; Hindlimb; Histones; Hypoxia; In Vitro; Inflammatory; Intervention; Ischemia; Knockout Mice; Kruppel-like transcription factors; Laboratories; Ligands; Limb structure; Macular degeneration; Malignant Neoplasms; Mediating; Microarray Analysis; Molecular; Mus; Myocardial Ischemia; Pathology; Pathway interactions; Phosphorylation; Play; Prevention; Process; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Rheumatoid Arthritis; Role; Signal Pathway; Signal Transduction; Testing; Therapeutic Effect; Transgenic Mice; Tube; Tumor Angiogenesis; Up-Regulation; Vascular Endothelial Growth Factors; angiogenesis; apoptotic protease-activating factor 1; base; blood vessel development; cancer therapy; caspase-3; caspase-9; cell motility; design; diabetic; in vivo; inhibitor/antagonist; insight; member; mouse model; mutant; notch protein; novel; novel therapeutic intervention; novel therapeutics; organ growth; prevent; protein kinase D; receptor; repaired; response; screening; therapeutic target

DESCRIPTION (provided by applicant): A considerable number of diseases, including ischemic heart and limb diseases, cancer, diabetic blindness, age-related macular degeneration and rheumatoid arthritis, are characterized by excessive or insufficient angiogenesis. Vascular endothelial growth factor (VEGF) is a major growth factor that regulates multiple endothelial cell (EC) functions and angiogenesis. The importance of VEGF in angiogenesis has offered new therapeutic opportunities. However, the incomplete understanding of the signaling pathways whereby VEGF directs angiogenesis remains a critical barrier to developing efficient anti-angiogenic cancer therapy or pro-angiogenic treatment for ischemic heart and limb diseases. Emerging evidence from my group and others supports a crucial role of protein kinase D (PKD1) in VEGF signaling and angiogenesis. PKD1 is a member of a novel family of serine/threonine protein kinases, which are potential druggable targets for therapeutics. As such, it is imperative to understand the biological functions of PKD1 and specific signaling events leading to angiogenesis. We are the first to report that VEGF via its receptor 2 stimulated PKD1 phosphorylation and activation in vascular ECs. Subsequently, we found that PKD1, via phosphorylation of histone deacetylases specifically HDAC7, regulates EC migration and tube formation. Nascent observations from my group now reveal that PKD1, through parallel effects on EC survival and new vessel formation, regulates VEGF-mediated angiogenesis. Specifically, using a PKD1 motif-based screening strategy, we identified a novel PKD1 substrate that is involved in the apoptosis pathway. Second, using gene profile analysis we have found that PKD1 is involved in the crosstalk of VEGF signaling and Notch signaling, which plays an essential role in new vessel formation including EC morphological differentiation, sprouting and vascular stabilization. Finally, our preliminary studies indicate that PKD1 inhibition impedes angiogenesis in vitro and in vivo. Therefore, our central hypothesis is that PKD1 activation by VEGF promotes endothelial survival and functions leading to angiogenesis. Three robust and interrelated aims are proposed to test this hypothesis: Aim 1. Determine the role and signaling mechanisms for PKD1 in VEGF-induced EC survival. Aim 2. Define the role and molecular mechanisms for PKD1 in the interplay of VEGF and Notch signaling. Aim 3. Study the role of PKD1 and signaling pathways in a mouse model of ischemia angiogenesis. Aim 4. Evaluate the biological role of PKD1 and therapeutic effects of a specific PKD inhibitor in a mouse model of tumor angiogenesis. The studies proposed herein will provide mechanistic insights and functional importance of the VEGF-PKD1 pathway in angiogenesis. The results of these studies will facilitate development of new therapeutic approaches to prevent or treat angiogenesis-related diseases.

描述（由申请人提供）：相当多的疾病，包括缺血性心脏和肢体疾病、癌症、糖尿病性失明、年龄相关性黄斑变性和类风湿性关节炎，其特征在于过度或不足的血管生成。血管内皮生长因子（VEGF）是一种主要的生长因子，调节多种内皮细胞（EC）功能和血管生成。VEGF在血管生成中的重要性提供了新的治疗机会。然而，对VEGF指导血管生成的信号传导途径的不完全理解仍然是开发有效的抗血管生成癌症疗法或缺血性心脏和肢体疾病的促血管生成疗法的关键障碍。来自我的小组和其他人的新证据支持蛋白激酶D（PKD 1）在VEGF信号传导和血管生成中的关键作用。PKD 1是丝氨酸/苏氨酸蛋白激酶新家族的成员，其是潜在的药物治疗靶标。因此，必须了解PKD 1的生物学功能和导致血管生成的特定信号事件。我们是第一个报道VEGF通过其受体2刺激血管内皮细胞中PKD 1磷酸化和活化的人。随后，我们发现PKD 1通过组蛋白去乙酰化酶的磷酸化，特别是HDAC 7，调节EC迁移和管形成。我的研究小组的初步观察显示，PKD 1通过对EC存活和新血管形成的平行作用，调节VEGF介导的血管生成。具体而言，使用PKD 1基序为基础的筛选策略，我们确定了一种新的PKD 1底物，参与细胞凋亡途径。其次，通过基因图谱分析，我们发现PKD 1参与VEGF信号和Notch信号的交叉，其在新血管形成包括EC形态分化、出芽和血管稳定中起重要作用。最后，我们的初步研究表明，PKD 1抑制在体外和体内阻碍血管生成。因此，我们的中心假设是VEGF激活PKD 1促进内皮细胞存活和功能，导致血管生成。提出了三个强大的和相互关联的目标来检验这一假设：目标1。确定PKD 1在VEGF诱导的EC存活中的作用和信号机制。目标2.明确PKD 1在VEGF和Notch信号传导相互作用中的作用和分子机制。目标3。研究PKD 1和信号通路在小鼠缺血血管生成模型中的作用。目标4。评价PKD 1的生物学作用和特定PKD抑制剂在肿瘤血管生成小鼠模型中的治疗作用。本文提出的研究将提供VEGF-PKD 1通路在血管生成中的机制见解和功能重要性。这些研究的结果将有助于开发新的治疗方法来预防或治疗血管生成相关疾病。