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），一种由大多数人类实体瘤产生的促血管生成因子，是重要的造血调节剂。 VEGF 信号传导对于早期造血发育至关重要。然而，包括我们在内的最新数据揭示了 VEGF 作为免​​疫细胞分化抑制剂的作用，对树突状 (DC) 和 T 细胞具有深远影响。我们做了一个重要的观察，即 VEGF 对 DC 的抑制作用的很大一部分是由酪氨酸激酶独立机制介导的。我们的初步数据强烈表明 VEGF 受体 1 (VEGFR1) 参与了这一过程。确定 VEGF 免疫抑制作用的具体机制对于开发针对癌症免疫校正的有效治疗策略至关重要。该项目的目标是研究该系统中抑制信号转导的机制和功能元件。 VEGF 配体或受体的大多数干扰都会导致胚胎致死，这使得造血效应的遗传学研究变得更加困难。因此，我们开发了体外系统，转基因小鼠胚胎干（ES）细胞可以分化为DC。我们将使用敲除各种受体并用特定受体突变体转导的鼠 ES 细胞来确定每个受体、其子结构域和信号传导伙伴在此过程中的作用。我们的动物骨髓移植研究旨在阐明每种 VEGF 受体及其酪氨酸激酶在体内 DC 功能障碍中的相对作用。我们假设 VEGFR1 是 DC 失调的主要介质，通过酪氨酸激酶依赖性以外的机制转导其抑制信号传导的大部分，涉及近膜结构域、异二聚体的形成或内化。我们将通过以下具体目标来测试这一点：1）表征VEGFR1非酪氨酸激酶亚结构域对DC分化和体外造血的作用。 2)确定VEGFR1酪氨酸磷酸化依赖性信号传导在体外DC缺陷中的作用。 3) 评估每种 VEGF 受体的信号传导在介导 VEGF 对 DC 体内发育的影响中的作用。了解 VEGF 信号在造血细胞中的机制和作用将有助于更深入地了解正常和病理性造血，以及旨在改善免疫功能和与癌症和免疫治疗高度临床相关的潜在治疗干预措施。