The Role of VEGF in Hematopoiesis in Cancer

VEGF 在癌症造血中的作用

• 批准号: 7016338
• 负责人: MIKHAIL M DIKOV
• 金额: $ 27.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-08 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7016338
• 关键词: T lymphocyte; biological signal transduction; bone marrow transplantation; cell differentiation; cell growth regulation; dendritic cells; embryonic stem cell; flow cytometry; gene deletion mutation; genetically modified animals; growth factor receptors; hematopoiesis; laboratory mouse; phosphorylation; protein structure function; protein tyrosine kinase; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Vascular Endothelial Growth Factor (VEGF), a pro-angiogenic factor produced by most human solid tumors is important modulator of hematopoiesis. VEGF signaling is crucial for early hematopoietic development. However, recent data including ours, revealed the role of VEGF as inhibitor of immune cell differentiation with profound effect on dendritic (DC) and T cells. We made an important observation that substantial part of VEGF inhibitory effect on DCs is mediated by tyrosine kinase-independent mechanism. Our preliminary data strongly implicate VEGF receptor 1 (VEGFR1) in this process. Identifying specific mechanisms of immunosuppressive effects of VEGF would be essential for the development of efficient therapeutic strategies aimed at immune correction in cancer. The goal of the proposed project is to investigate the mechanism and functional elements of inhibitory signal transduction in this system. The embryonic lethality of most perturbations of VEGF ligand or receptors makes genetic studies of hematopoietic effects more difficult. We have therefore developed in vitro system where genetically modified murine embryonic stem (ES) cells can be differentiated into DCs. We will use murine ES cells knocked out for various receptors and transduced with specific receptor mutants to determine the role of each receptor, their subdomains and signaling partners in this process. Our animal bone marrow transplant studies are designed to elucidate relative contribution of each VEGF receptor and their tyrosine kinases in DC dysfunction in vivo. We hypothesize that VEGFR1 being a major mediator of DC dysregulation transduces substantial part of its inhibitory signaling by mechanism other then tyrosine kinase-dependent, involving juxtamembrane domain, formation of heterodimers, or internalization. We will test this by the following specific aims: 1) Characterize the roles of VEGFR1 non-tyrosine kinase subdomains on DC differentiation and hematopoiesis in vitro. 2) Determine the role of VEGFR1 tyrosine phosphorylation dependent signaling in DC defects in vitro. 3) Assess the role of signaling by each VEGF receptors in mediating VEGF effects on DC development in vivo. Understanding the mechanism and effects of VEGF signaling in hematopoietic cells will lead to greater insight into normal and pathological hematopoiesis, and potential therapeutic interventions aimed at improvement of immune function and highly clinically relevant to cancer and immunotherapy.

描述（由申请人提供）：血管内皮生长因子（VEGF），大多数人类实体瘤产生的促血管生成因子是造血的重要调节剂。 VEGF信号传导对于早期造血发育至关重要。但是，最近的数据在内的数据揭示了VEGF作为免疫细胞分化的抑制剂，对树突状（DC）和T细胞产生深远影响。我们做出了一个重要的观察，即VEGF抑制作用对DC的大部分部分是由酪氨酸激酶独立的机制介导的。在此过程中，我们的初步数据强烈暗示VEGF受体1（VEGFR1）。确定VEGF免疫抑制作用的特定机制对于开发旨在用于癌症免疫矫正的有效治疗策略至关重要。拟议项目的目的是研究该系统抑制信号转导的机制和功能元素。 VEGF配体或受体大多数扰动的胚胎致死性使造血作用的遗传研究更加困难。因此，我们已经开发了体外系统，在该系统中，可以将基因修饰的鼠类胚胎（ES）细胞分化为DC。我们将使用被撞倒的鼠ES细胞作为各种受体并用特定受体突变体转导，以确定每个受体，它们的亚域和信号伴侣在此过程中的作用。我们的动物骨髓移植研究旨在阐明每个VEGF受体及其在体内DC功能障碍中的相对贡献。我们假设VEGFR1是DC失调的主要介体，它通过机制通过其他酪氨酸激酶依赖性的机制传递了其抑制性信号的大部分，涉及近去膜结构域，形成异二聚体或内在化。我们将通过以下特定目的进行测试：1）表征VEGFR1非酪氨酸激酶子域在体外DC分化和造血的作用。 2）确定VEGFR1酪氨酸磷酸化信号传导在体外DC缺陷中的作用。 3）评估每个VEGF受体在介导VEGF对体内DC发育影响的信号传导的作用。了解VEGF信号在造血细胞中的机制和作用将导致对正常和病理造血的深入了解，以及旨在改善免疫功能并与癌症和免疫疗法高度相关的潜在治疗干预措施。