Phosphoinositide Signaling Regulates Melanogenesis

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有害影响的皮肤色素，在一种称为黑素体的专门的溶酶体相关细胞器中合成。黑素体成熟通过将合成黑素的酶顺序递送到发育中的细胞器来精确控制，使得黑素合成仅发生在III或IV期黑素体中。黑素体成熟缺陷与皮肤癌易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递送到黑素体的囊泡运输途径，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。在本申请中，我们假设磷酸肌醇信号传导协调黑素体成熟与产生黑素的酶的转录。拟议的研究将：1）识别将运输囊泡引导至黑素体的脂质信号; 2）识别引导运输囊泡不与自噬体或黑素体融合的细胞信号; 3）确定细胞如何协调黑素体成熟与产生黑素的酶的转录，并检查该途径在结节性硬化症中的相关性。完成拟议的研究不仅将增强我们对细胞内囊泡转运如何协调和划分的基本理解，而且还将导致设计药理学药物来刺激皮肤癌易感患者的黑素体成熟，减少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.