TYROSINASE RELATED PROTEIN-1 AND BROWN OCA

描述：(改编自申请人的摘要)-Trp-1，成员 与黑色素有关的黑素细胞特异性基因产物家族 合成，是一个科学之谜。在这组分子中，色氨酸-1是 偶然被几个试图克隆的独立组织识别 酪氨酸酶，c-位点蛋白。Trp-1的揭开面纱是因为 针对酪氨酸酶产生的抗血清在当时并不为人所知， 与Trp-1发生交叉反应。这说明了另一个有趣的特性 Trp-1，一种细胞内蛋白：它似乎具有极强的免疫原性。 已鉴定出抗Trp-1的血清抗体和自身反应性T细胞 在黑色素瘤患者身上。此外，色氨酸蛋白-1抗体的出现 与白癜风在鸟类模型中的表达有关，Smyth 鸡肉。有趣的是，有报道称自身抗体识别一个 75kDa的糖蛋白(M.W.Trp-1)在白癜风患者中的表达 可能是Trp-1。然而，尽管Trp-1在 科学/医学研究，色氨酸-1在黑素生成中的作用一直是 难以捉摸。申请者确信Trp-1的突变会导致 在小鼠身上合成棕色而不是黑色的毛皮。然而，它的作用是 人类头发中的Trp-1，以及皮肤中的色素沉着或Trp-1如何突变 对这些组织的影响，目前还没有阐明。 申请者建议分析Trp-1在人类免疫缺陷中的分子作用 用三种途径研究黑色素的合成。首先，他们会 Trp-1对酪氨酸酶/Trp-1催化功能的调节作用 和/或Trp-2，物理上与酪氨酸酶/Trp-2相互作用，并表达 利用确定的黑色素瘤细胞和成纤维细胞推测的催化功能(S) Trp-1基因的导入及红娘双杂交系统的建立 分析蛋白质相互作用。第二，分子的突变图谱 将讨论负责TRP-1这些功能的域。第三, 酪氨酸酶阳性OCA表达突变患者的黑素细胞 影响Trp-1，以及在棕色基因座上携带突变等位基因的小鼠， 将被分析为黑色素合成的缺陷。这些研究将 阐明色氨酸蛋白-1的功能及其与其他蛋白的相互作用 黑素细胞特异性基因产物及其在青光眼病理生理学中的作用 人类色素性疾病，特别是棕色OCA。这些研究还将 有助于我们了解黑素生成和黑素细胞的作用 在皮肤里。

DESCRIPTION: (Adapted from the applicant's abstract) - TRP-1, a member of the family of melanocyte-specific gene products involved in melanin synthesis, is a scientific enigma. Of the group of molecules, TRP-1 was identified serendipitously by several independent groups attempting to clone tyrosinase, the c-locus protein. This unveiling of TRP-1 resulted because antisera generated against tyrosinase had, unbeknownst at the time, cross-reacted with TRP-1. This illustrates another interesting feature of TRP-1, an intracellular protein: it appears to be extremely immunogenic. Serum antibodies and autoreactive T-cells against TRP-1 have been identified in patients with melanoma. Also, the appearance of TRP-1 antibodies correlates with the expression of vitiligo in an avian model, the Smyth chicken. Of interest are reports of autoantibodies recognizing a glycoprotein of 75 kDA (the m.w. of TRP-1) in patients with vitiligo which may be TRP-1. However, despite the prominence of TRP-1 in scientific/medical research, the role of TRP-1 in melanogenesis has been elusive. The applicants are certain that mutations of TRP-1 result in the synthesis of brown as opposed to black pelage in mice. However, the role of TRP-1 in human hair, as well as skin, pigmentation or how mutations in TRP-1 affect these tissues, has not been elucidated. The applicants propose to analyze the molecular role of TRP-1 in the synthesis of melanin using three avenues of investigation. First they will investigate how TRP-1 regulates the catalytic function of tyrosinase/TRP-1 and/or TRP-2, physically interacts with tyrosinase/TRP-2, and expresses a putative catalytic function(s) using defined melanoma cells and fibroblasts transfected with TRP-1 cDNA and the Matchmaker Two-Hybrid System for analyzing protein interactions. Second, mutational mapping of molecular domains responsible for these functions of TRP-1 will be addressed. Third, melanocytes from patients with tyrosinase-positive OCA expressing mutations affecting TRP-1, and from mice carrying mutant alleles at the brown locus, will be analyzed for defects in melanin synthesis. These studies will elucidate the function of TRP-1, its interaction with other melanocyte-specific gene products, and its role in the pathophysiology of human pigmentary diseases, specifically Brown OCA. These studies will also contribute to our knowledge of melanogenesis and the role of the melanocyte in the skin.