Phosphoinositide Signaling Regulates Melanogenesis

磷酸肌醇信号调节黑色素生成

• 批准号: 8826025
• 负责人: Anand K Ganesan
• 金额: $ 38.01万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8826025
• 关键词: Albinism; Autophagocytosis; Autophagosome; Binding; Binding Proteins; Biological; Cell Death; Cells; DNA Damage; Defect; Development; Disease; Enzymes; Eye; Genetic Transcription; Health; Hermanski-Pudlak Syndrome; In Vitro; Individual; Knowledge; Lead; Link; Lipids; Lysosomes; Melanins; Melanogenesis; Melanoma Cell; Melanosomes; Membrane; Metabolism; Monophenol Monooxygenase; Mus; Organelles; Pathway interactions; Patients; Phosphatidylinositols; Pigments; Predisposition; Process; Protein Binding; Proteins; RNA Interference; Relative (related person); Role; Signal Pathway; Signal Transduction; Skin; Skin Cancer; Skin Carcinoma; Specific qualifier value; Staging; Transport Vesicles; Tuberous Sclerosis; UV induced; United States; Variant; Vesicle; Vesicle Transport Pathway; Work; burden of illness; cancer type; design; human FRAP1 protein; human disease; in vivo; innovation; novel; research study; small hairpin RNA

DESCRIPTION (provided by applicant): Melanin, a skin pigment that protects the skin and eyes from the harmful effects of UV, is synthesized in a specialized lysosome-related organelle called the melanosome. Melanosome maturation is precisely controlled by the sequential delivery of enzymes that synthesize melanin to the developing organelle such that melanin synthesis only occurs in the stage III or IV melanosome. Defects in melanosome maturation are linked to skin cancer susceptibility and skin pigment variation, highlighting the intrinsic biologial relevance of this pathway. While extensive studies have identified vesicle transport pathways that deliver proteins to the melanosome, little is known about what directs transport vesicles to fuse with the developing melanosome. Recent work from our group has identified specific lipid signals that direct vesicles to fuse with the melanosome. In this application, we hypothesize that phosphoinositide signaling coordinates melanosome maturation with the transcription of enzymes that produce melanin. The studies proposed will: 1) identify lipid signals that direct transport vesicles to the melanosome; 2) identify cellular signals that direct transport vesicles t fuse with autophagosomes or melanosomes; 3) determine how cells coordinate melanosome maturation with the transcription of enzymes that produce melanin and examine the relevance of this pathway in tuberous sclerosis. Completion of the proposed studies will not only enhance our fundamental understanding of how intracellular vesicle transport is coordinated and compartmentalized, but will also lead to the design of pharmacologic agents to stimulate melanosome maturation in skin cancer susceptible patients, reducing the disease burden of the most common type of cancer in the United States.

描述（由申请人提供）：黑色素是一种皮肤色素，可以保护皮肤和眼睛免受紫外线的有害影响，是在一种叫做黑素小体的特殊溶酶体相关细胞器中合成的。黑色素小体的成熟是由合成黑色素的酶向发育中的细胞器的顺序传递精确控制的，因此黑色素合成只发生在黑色素小体的第三或第四阶段。黑色素小体成熟的缺陷与皮肤癌易感性和皮肤色素变异有关，突出了这一途径的内在生物学相关性。虽然广泛的研究已经确定了将蛋白质运送到黑素小体的囊泡运输途径，但对于是什么引导运输囊泡与发育中的黑素小体融合知之甚少。我们小组最近的工作已经确定了指导囊泡与黑素体融合的特定脂质信号。在这个应用中，我们假设磷脂肌肽信号通过产生黑色素的酶的转录来协调黑素小体的成熟。建议的研究将：1)识别直接运输囊泡到黑素小体的脂质信号；2)识别直接运输囊泡与自噬体或黑素小体融合的细胞信号；3)确定细胞如何协调黑色素小体成熟与产生黑色素的酶的转录，并检查这一途径在结节性硬化症中的相关性。完成所提出的研究不仅将增强我们对细胞内囊泡运输如何协调和区分开的基本理解，而且还将导致设计药物来刺激皮肤癌易感患者的黑素小体成熟，减少美国最常见的癌症类型的疾病负担。