Molecular regulation of angiogenesis

血管生成的分子调控

• 批准号: 8341247
• 负责人: ZHENG-GEN JIN
• 金额: $ 38.63万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8341247
• 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; 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; Organ; Pathology; Pathway interactions; Phosphorylation; Play; Prevention; Process; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Rheumatoid Arthritis; Role; Screening procedure; 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; 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; prevent; protein kinase D; receptor; repaired; response; 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. PUBLIC HEALTH RELEVANCE: A considerable number of diseases, including ischemic heart and limb diseases, cancer, diabetic blindness, age-related macular degeneration and rheumatoid arthritis, are characterized by either excessive or insufficient angiogenesis. The studies proposed in this project are designed to elucidate the role of a protein called PKD1 in regulation of vascular endothelial function and new blood vessel formation. The findings from this project will provide a better understanding of cellular signaling mechanisms underlying abnormal blood vessel formation, and will provide an underpinning for the advancement of more effectively targeted interventions aimed at angiogenesis-associated 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、糖尿病失明、年龄相关性黄斑变性和类风湿性关节炎，其特征是血管生成过度或不足。血管内皮生长因子（VEGF）是调节多种内皮细胞（EC）功能和血管生成的主要生长因子。 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通路的不完全了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治疗的关键障碍。我的团队和其他人的新证据支持蛋白激酶 D (PKD1) 在 VEGF 信号传导和血管生成中的关键作用。 PKD1 是丝氨酸/苏氨酸蛋白激酶新家族的成员，该家族是潜在的药物治疗靶点。因此，有必要了解 PKD1 的生物学功能和导致血管生成的特定信号事件。我们首次报道 VEGF 通过其受体 2 刺激血管 EC 中的 PKD1 磷酸化和激活。随后，我们发现 PKD1 通过组蛋白脱乙酰酶（特别是 HDAC7）的磷酸化来调节 EC 迁移和管形成。我的团队的初步观察结果表明，PKD1 通过对 EC 存活和新血管形成的平行影响，调节 VEGF 介导的血管生成。具体来说，使用基于 PKD1 基序的筛选策略，我们鉴定了一种参与细胞凋亡途径的新型 PKD1 底物。其次，通过基因谱分析，我们发现 PKD1 参与 VEGF 信号和 Notch 信号的串扰，在新血管形成中发挥重要作用，包括 EC 形态分化、出芽和血管稳定。最后，我们的初步研究表明 PKD1 抑制会阻碍体外和体内的血管生成。因此，我们的中心假设是 VEGF 激活 PKD1 促进内皮细胞存活和功能，从而导致血管生成。提出了三个强有力且相互关联的目标来检验这一假设： 目标 1. 确定 PKD1 在 VEGF 诱导的 EC 存活中的作用和信号机制。目标 2. 明确 PKD1 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 PKD1 和信号通路在小鼠缺血血管生成模型中的作用。目标 4. 在肿瘤血管生成小鼠模型中评估 PKD1 的生物学作用和特定 PKD 抑制剂的治疗效果。本文提出的研究将提供 VEGF-PKD1 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。 公众健康相关性：相当多的疾病，包括缺血性心脏和肢体疾病、癌症、糖尿病失明、年龄相关性黄斑变性和类风湿性关节炎，其特征是血管生成过度或不足。该项目提出的研究旨在阐明一种名为 PKD1 的蛋白质在调节血管内皮功能和新血管形成中的作用。该项目的研究结果将有助于更好地理解异常血管形成背后的细胞信号传导机制，并将为针对血管生成相关疾病的更有效的针对性干预措施的进展提供基础。