Phosphoinositide Signaling Regulates Melanogenesis

描述(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，它是在一种专门的溶酶体相关细胞器中合成的，称为黑素小体。黑素小体的成熟是由合成黑色素的酶依次递送到发育中的细胞器来控制的，因此黑色素合成只发生在第三或第四阶段的黑素小体中。黑素小体成熟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输送到黑素小体的囊泡运输途径，但对是什么引导运输小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引导小泡与黑素小体融合的特定脂质信号。在这个应用中，我们假设肌醇磷脂信号与产生黑色素的酶的转录协调黑素小体的成熟。建议的研究将：1)确定直接将小泡运输到黑素小体的脂类信号；2)确定直接运输小泡的细胞信号；3)确定细胞如何协调黑素小体成熟和产生黑色素的酶的转录，并研究这一途径在结节性硬化症中的相关性。拟议研究的完成不仅将增强我们对细胞内囊泡运输是如何协调和划分的基本了解，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，从而减轻美国最常见类型癌症的疾病负担。

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.