Biogenesis of Melanosomes

黑素体的生物发生

• 批准号: 8538704
• 负责人: SETH J. ORLOW
• 金额: $ 4.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538704
• 关键词: Accounting; Address; Adjuvant; Albinism; Apoptosis; Apoptotic; Autoimmune Diseases; Autophagocytosis; Biogenesis; Cell Death; Cells; Cessation of life; Chemicals; Cutaneous; Data; Development; Diabetes Mellitus; Disease; Dopa; Endoplasmic Reticulum; Enzymes; Eye; Gene Mutation; Genetic Polymorphism; Golgi Apparatus; Hereditary Disease; Homeostasis; Hypopigmentation; Immune response; Insulin-Dependent Diabetes Mellitus; Investigation; Lead; Macular degeneration; Malignant Neoplasms; Melanins; Melanosomes; Modality; Molecular Chaperones; Monophenol Monooxygenase; Mus; Mutation; Oculocutaneous Albinism; Optic tract structure; Pancreas; Pathogenesis; Pathway interactions; Pigmentation physiologic function; Pigments; Play; Post-Translational Protein Processing; Predisposition; Process; Production; Proteins; Radiation induced damage; Reaction; Regulation; Retinitis; Risk; Risk Factors; Role; Signal Transduction Pathway; Skin; Skin Cancer; Skin Pigmentation; Testing; Therapeutic Agents; Tyrosinase related protein-1; Tyrosine; Ultraviolet Rays; Vitiligo; X-Linked Retinoschisis; design; endoplasmic reticulum stress; enzyme activity; human TYRP1 protein; improved; mRNA Expression; melanocyte; melanoma; mutant; prevent; primary congenital glaucoma; protein expression; protein folding; protein misfolding; response; small molecule; small molecule libraries; therapy development

DESCRIPTION (provided by applicant): Melanin protects skin against ultraviolet radiation-induced damage, thus reducing risk of cutaneous cancers. Our primary objective is to elucidate the mechanisms that regulate melanin synthesis and characterize the pathogenesis of pigmentary disorders. We will focus on tyrosinase, the enzyme that catalyzes the first, rate-limiting step in melanin synthesis, namely conversion of L-tyrosine to dihydroxyphenylalanine. Tyrosinase is a determinant of skin pigmentation and risk of cutaneous cancers. Tyrosinase has also been implicated in genetic disorders such as oculocutaneous albinism (OCA), in autoimmune diseases such as vitiligo, and in melanoma, and may be a modifier locus for primary congenital glaucoma and macular degeneration in X-linked retinoschisis. While tyrosinase activity varies as much as ten-fold in lightly versus darkly pigmented skin, mRNA and protein expression levels are remarkably similar. Instead, post-translational modification of tyrosinase is key for its regulation and activity. Disruption of tyrosinase folding has been implicated in 3 of the 4 major forms of OCA and may contribute to the immune response against melanocytes or melanoma. In Specific Aim 1, we will elucidate the mechanisms underlying post-translational modification of tyrosinase and characterize the roles of the OCA-related proteins as well as protein chaperones in this process. We will also examine the effects of tyrosinase polymorphisms - such as those associated with vitiligo and melanoma risk - on protein folding and enzyme activity. OCA mutations cause accumulation of tyrosinase in the Endoplasmic reticulum (ER), triggering the unfolded protein response (UPR). We have shown that melanocytes adapt to sustained ER stress. In Specific Aim 2, we will continue our investigation of the melanocyte UPR and determine how melanocytes evade apoptosis that is typical of sustained UPR activation. Recent studies suggest that UPR-modulating agents can increase the efficacy of chemotherapeutics. Understanding ER stress and the UPR in melanocytes may thus be critical in the design of adjuvants for melanoma therapies. In Specific Aim 3, we will investigate and assess whether chemical chaperones that promote protein folding improve tyrosinase maturation, particularly in the absence of OCA-related proteins. Such compounds hold promise for the development of therapeutic agents for the OCAs. These studies will greatly advance our understanding of the regulation of skin pigmentation (a major risk factor for skin cancer) and pathogenesis of pigment disorders such as OCA and vitiligo.

描述（由申请人提供）：黑色素保护皮肤免受紫外线辐射引起的损伤，从而降低皮肤癌的风险。我们的主要目标是阐明调节黑色素合成的机制，并描述色素性疾病的发病机制。我们将集中在酪氨酸酶，催化黑色素合成的第一个限速步骤，即L-酪氨酸转化为二羟基苯丙氨酸的酶。酪氨酸酶是皮肤色素沉着和皮肤癌风险的决定因素。酪氨酸酶也与遗传性疾病如眼皮肤白化病（OCA）、自身免疫性疾病如白癜风和黑色素瘤有关，并且可能是X连锁视网膜劈裂症中原发性先天性青光眼和黄斑变性的修饰基因座。虽然酪氨酸酶活性在浅色皮肤与深色皮肤中变化多达10倍，但mRNA和蛋白质表达水平非常相似。相反，酪氨酸酶的翻译后修饰是其调节和活性的关键。酪氨酸酶折叠的破坏与OCA的4种主要形式中的3种有关，并可能有助于对黑素细胞或黑色素瘤的免疫应答。 在具体目标1中，我们将阐明酪氨酸酶的翻译后修饰的机制，并表征在这一过程中的OCA相关蛋白以及蛋白伴侣的作用。我们还将研究酪氨酸酶多态性对蛋白质折叠和酶活性的影响，例如与白癜风和黑色素瘤风险相关的多态性。OCA突变导致酪氨酸酶在内质网（ER）中积累，触发未折叠蛋白反应（UPR）。我们已经表明，黑素细胞适应持续的ER压力。在具体目标2中，我们将继续我们的黑素细胞UPR的调查，并确定黑素细胞如何逃避细胞凋亡，这是典型的持续UPR激活。最近的研究表明，UPR调节剂可以增加化疗药物的疗效。因此，了解黑素细胞中的ER应激和UPR可能对设计黑色素瘤治疗的佐剂至关重要。在具体目标3中，我们将研究和评估促进蛋白质折叠的化学分子伴侣是否改善酪氨酸酶成熟，特别是在缺乏OCA相关蛋白的情况下。此类化合物有望开发OCA的治疗剂。这些研究将极大地推进我们对皮肤色素沉着（皮肤癌的主要危险因素）的调节和色素疾病（如OCA和白癜风）的发病机制的理解。