NEW PATHWAY LIMITS CELLULAR CHOLESTEROL CONTENT

新途径限制细胞胆固醇含量

• 批准号: 2031190
• 负责人: PHOEBE E FIELDING
• 金额: $ 34.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2031190
• 关键词: binding proteins; biological transport; cell biology; cell line; cholesterol; cytoplasm; gene induction /repression; high density lipoproteins; human tissue; low density lipoprotein; lymphatic tissue; macrophage; messenger RNA; transfection; vesicle /vacuole

DESCRIPTION (Adapted from Investigator's Abstract): Normal cells control their cholesterol content within narrow limits. If cholesterol uptake increases, cholesterol efflux is also increased to keep cell cholesterol content the same. If this response is inhibited, free and esterified cholesterol accumulate in the cell. Foam cell formation reflects a failure of this regulatory pathway. The molecular basis of this reflexive cholesterol unloading and its regulation will be determined. We recently observed that caveolae, which are cholesterol-rich cell surface microdomains, are the terminus of the cholesterol efflux pathway to high density lipoprotein. The presence of caveolae at the cell surface is recognized to depend on caveolin, a 22kDa cholesterol-binding protein. Four Specific Aims deal with different aspects of the molecular and cell biology of caveolae related to cholesterol transport and efflux. In the first Specific Aim, the mechanism of induction of caveolin mRNA in response to cholesterol loading by low density lipoprotein will be determined. In the second Specific Aim, human lymphoid cells which lack endogenous caveolin will be stably transfected with human caveolin cDNA. Its effects on the ability of these cells to regulate their cholesterol content will be determined. In the third Specific Aim, the intracellular lipid vesicles that carry cholesterol to the caveolae will be fully characterized, as will the cytoplasmic factors required for cholesterol transport. In the last Specific Aim, the identity of a factor, possibly related to cellubrevin, which targets intracellular cholesterol to the cell surface caveolae, will be established. These studies will provide novel basic information on the biology of cellular cholesterol homeostasis. They will also identify new targets for intervention in promoting the unloading of cholesterol-filled cells.

描述（根据研究者的摘要改编）：正常细胞控制 他们的胆固醇含量在狭窄的极限内。 如果胆固醇摄取 增加，胆固醇外排也增加以保持细胞胆固醇 内容相同。 如果这种响应被抑制，免费和酯化 胆固醇积聚在细胞中。 泡沫细胞形成反映了失败 该法规途径。 这种反射性的分子基础 将确定胆固醇卸载及其调节。 我们最近 观察到富含胆固醇的细胞表面的小窝 微域是胆固醇外排的末端 密度脂蛋白。 小屋在细胞表面的存在是 公认依赖可窝蛋白，这是一种22KDA胆固醇结合蛋白。 四个 具体目的涉及分子和细胞生物学的不同方面 与胆固醇运输和外排有关的小窝。 在第一个 特定目的，诱导小窝蛋白mRNA的机理 将确定低密度脂蛋白的胆固醇载荷。 在 第二个特定目的，缺乏内源性小窝蛋白的人淋巴细胞 将稳定地用人的小窝蛋白cDNA转染。 它对 这些细胞调节其胆固醇含量的能力将是 决定。 在第三个特定目标中，细胞内脂质囊泡 将胆固醇带到小窝的胆固醇将得到充分表征， 胆固醇转运所需的细胞质因子。 在最后 特定目的，一个因子的身份，可能与Cellubrevin相关， 将细胞内胆固醇靶向细胞表面小窝，将 建立。 这些研究将为有关 细胞胆固醇稳态的生物学。 他们还将确定新的 干预促进胆固醇填充的目标 细胞。