GROWTH FACTORS AND MECHANISM OF CELLULAR POLIFERATION

细胞增殖的生长因子和机制

• 批准号: 2089128
• 负责人: JAMES P TAM
• 金额: $ 26.54万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2089128
• 关键词: athymic mouse; cell growth regulation; cell type; chemical structure function; chemical synthesis; drug screening /evaluation; epidermal growth factor; growth factor; growth factor receptors; inhibitor /antagonist; interleukin 1; laboratory rabbit; transforming growth factors

Epidermal growth factor (EGF)/transforming growth factor alpha (TGFalpha) is one of the most widely distributed families of growth factors in the body. They are potent mitogens and angiogenic factors that have been implicated to promote tumor growth and wound healing. Interleukin 1 alpha and beta (IL-1) are ubiquitous cytokines that mediate inflammation as well as normal or abnormal cell growth and development. The primary goals of this project are two fold. First, the proposed research will develop cell- type antagonists of these two growth factor families for the therapeutic intervention. The EGFs and IL-1 are particularly suitable targets since they may share similar principles in the design of their antagonist. Second, they are aimed to expand the peptide chemistry for the rational design of growth factors and to use these antagonists for biochemical studies. These will include the chemical goals of developing the domain ligation strategy and defining approaches for the design of antagonist, as, well as the biological goal of applying growth factor antagonists to study the cellular signal transduction mechanism that will aid the rational design of growth factor antagonists. In general, the goals of this project will be built upon the progress and leads made during the present period. The specific aims are as follows: 1. Design and synthesis of antagonists of EGF/TGFalpha and IL1. 2. Develop domain ligation strategy for the synthesis of growth factor antagonists and mosaic proteins. 3. Develop mosaic growth factors that confer cell type selectivity. 4. Determine the structures of selected growth factor antagonists by 2D NMR. 5. Use EGF antagonists to study endogenous substrates and to identify the signal transduction mechanism of EGF receptor and to help the rational design of EGF antagonists. 6. Study of in vivo efficacy of EGF antagonists in nude mice.

表皮生长因子 (EGF)/转化生长因子 α (TGFα) 是生长因子家族中分布最广泛的家族之一 身体。它们是有效的有丝分裂原和血管生成因子，已被 与促进肿瘤生长和伤口愈合有关。白细胞介素1α 和 β (IL-1) 是普遍存在的细胞因子，也介导炎症 正常或异常的细胞生长和发育。主要目标 这个项目有两个部分。首先，拟议的研究将开发细胞 这两个生长因子家族的拮抗剂用于治疗 干涉。 EGF 和 IL-1 是特别合适的靶标，因为 他们在设计对手时可能有相似的原则。 其次，他们的目的是扩大肽化学的合理范围 生长因子的设计以及使用这些拮抗剂进行生化研究 研究。这些将包括开发该领域的化学目标 连接策略和拮抗剂设计的定义方法， 以及应用生长因子拮抗剂的生物学目标 研究细胞信号转导机制，这将有助于 合理设计生长因子拮抗剂。一般来说，目标 该项目将建立在 当前时期。具体目标如下： 1. EGF/TGFα和IL1拮抗剂的设计与合成。 2. 制定生长因子合成的域连接策略 拮抗剂和嵌合蛋白。 3. 开发赋予细胞类型选择性的镶嵌生长因子。 4. 通过 2D 确定所选生长因子拮抗剂的结构 核磁共振。 5. 使用 EGF 拮抗剂研究内源性底物并鉴定 EGF受体信号转导机制及帮助理性 EGF拮抗剂的设计。 6、EGF拮抗剂裸鼠体内药效研究。