Design of Membrane-Associated Signaling Modulators

膜相关信号调制器的设计

• 批准号: 6681564
• 负责人: JAMES P TAM
• 金额: $ 15.1万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6681564
• 关键词: biological signal transduction; biomimetics; biotechnology; endocytosis; guanine nucleotide binding protein; membrane permeability; protein engineering; protein protein interaction; protein signal sequence; protein transport; reagent /indicator; vesicle /vacuole

DESCRIPTION (provided by applicant): Ras proteins are membrane-associated proteins that modulate cell activation by acting as a molecular "on-off" switch of many receptor-coupled signaling pathways. Mutations of Ras protein leading to an activated state are found in about 25 % of oncogenic transformation. Certain Ras proteins also interacts with caveolin-1, a cholesterol-binding membrane protein that regulates cellular trafficking through a specific lipid microdomain (lipid raft) linked to receptorcoupled signal cascades. Both types of proteins contain lipids and membrane-binding domains for their membrane-associated functions. This application will focus on the development of Ras protein mimetics that are capable of membrane-tanslocation and membrane-association to modulate Ras signaling pathways. The key design of the Ras mimetics is a novel membrane permeable alpha/epsilon-peptide dendron with or without fatty acylated chains that function as transportants. Our immediate goals include the development of a novel synthetic platform based on tandem ligation for preparing reagents consisting of detection probes, membranepermeable dendrons, peptide cargoes or lipids to facilitate assays and mechanistic study in our experiments. The development of an effective strategy for targeting regulated intracellular delivery of macromolecules represents a long-term objective of our application. To achieve our goals, this application will use both chemical and biological tools. Specific Aim #1 will develop reagents and a synthetic platform for preparing Ras protein mimetics. Aims #2 and #3 will evaluate soluble membrane-permeable and membrane-associated Ras mimetics to inhibit Ras effectors and their association in lipid rafts. Aim #4 will compare the delivery mechanisms of Ras mimetics through endosomal pathway.

描述（由申请人提供）：Ras蛋白是膜相关蛋白，其通过充当许多受体偶联信号通路的分子“开关”来调节细胞活化。在大约 25% 的致癌转化中发现了导致激活状态的 Ras 蛋白突变。某些 Ras 蛋白还与 Caveolin-1 相互作用，caveolin-1 是一种胆固醇结合膜蛋白，可通过与受体偶联信号级联相连的特定脂质微结构域（脂筏）调节细胞运输。两种类型的蛋白质都含有脂质和膜结合域以实现其膜相关功能。该应用将重点开发能够通过膜易位和膜结合来调节 Ras 信号通路的 Ras 蛋白模拟物。 Ras 模拟物的关键设计是一种新型膜渗透性 α/ε 肽树突，具有或不具有作为转运蛋白的脂肪酰化链。我们的近期目标包括开发一种基于串联连接的新型合成平台，用于制备由检测探针、透膜树突、肽货物或脂质组成的试剂，以促进我们实验中的测定和机制研究。开发一种有效的策略来靶向调控大分子的细胞内递送是我们应用的长期目标。为了实现我们的目标，该应用程序将使用化学和生物工具。具体目标#1 将开发用于制备 Ras 蛋白模拟物的试剂和合成平台。目标 #2 和 #3 将评估可溶性膜渗透性和膜相关 Ras 模拟物，以抑制 Ras 效应器及其在脂筏中的关联。目标 #4 将比较 Ras 模拟物通过内体途径的递送机制。