Phosphoinositide Signaling Regulates Melanogenesis

磷酸肌醇信号调节黑色素生成

• 批准号: 8456852
• 负责人: Anand K Ganesan
• 金额: $ 33.2万
• 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 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8456852
• 关键词: Albinism; Autophagocytosis; Autophagosome; Binding; Binding Proteins; Biological; Cell Death; Cells; DNA Damage; Defect; Development; Disease; Enzymes; Eye; Genetic Transcription; Hermanski-Pudlak Syndrome; In Vitro; Individual; Intracellular Transport; 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; public health relevance; 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）：黑色素是一种保护皮肤和眼睛免受紫外线效果的皮肤色素，在一种称为黑色素体的专门溶酶体相关细胞器中合成。黑色素体的成熟由将黑色素合成到发育中的细胞器的酶的顺序递送精确控制，使得黑色素合成仅发生在III期或IV期黑色素体中。黑色素体成熟的缺陷与皮肤癌的敏感性和皮肤色素变异有关，突出了该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输送到黑色素体的囊泡传输途径，但对指导转运囊泡与发育中的黑素体融合的是什么知之甚少。我们小组的最新工作确定了将囊泡与黑色素体融合的特定脂质信号。在此应用中，我们假设磷酸肌醇信号传导将黑色素体成熟与产生黑色素的酶的转录。提出的研究将：1）确定将囊泡直接运输到黑色素体的脂质信号； 2）确定将囊泡与自噬体或黑色素体融合的细胞信号； 3）确定细胞如何与产生黑色素的酶的转录来协调黑色素体的成熟，并检查该途径在结节硬化中的相关性。拟议研究的完成不仅将增强我们对细胞内囊泡运输方式如何协调和分隔的基本理解，而且还将导致设计药理学剂以刺激皮肤癌敏感患者的黑色素体成熟，从而减轻美国癌症中最常见的类型类型的疾病负担。