MELANOGENIC CORRELATES OF AGOUTI GENE EXPRESSION

AGOUTI 基因表达的黑色素生成相关性

• 批准号: 2082213
• 负责人: NELS H GRANHOLM
• 金额: $ 10.42万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-07-10 至 2000-07-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2082213
• 关键词: biological signal transduction; diabetes mellitus genetics; fertility; gene expression; immunosuppression; laboratory mouse; lethal genes; melanins; melanocyte; melanoma; melanosomes; molecular pathology; monophenol monooxygenase; northern blottings; obesity; pigmentation disorders; western blottings

Our broad, long-term objective is to determine why mutations of the murine agouti locus like lethal yellow (Ay) and viable yellow (Avy) cause pathologies of the Lethal Yellow Syndrome (LYS)-obesity, aberrant pigmentation, cancer, enhanced growth, immunosuppression, infertility, and diabetes. The agouti locus regulates the type of pigment (black and/or yellow) synthesized within follicular melanocytes (Silvers, 19790. Agouti alleles alter specific melanogenic parameters (Ito, 1993; Tamate et al., 1989; Granholm et al., 1990b). With the advent of agouti gene isolation, cloning, sequencing, and partial characterization (Bultman et al., 1992; Miller et al., 1993), we now for the first time have an opportunity to correlate the molecular events of melanogenesis with virtually unequivocal evidence of agouti expression (i.e., presence of agouti transcripts followed by synthesis of agouti proteins). Specific Aims include: 1) Developmental Northern analyses together with specific assays of melanogenesis (tyrosinase (both tyrosine hydroxylase and dopa oxidase), type of melanin (total, eu-, and phaeomelanin), dopachrome tautomerse (DT), and melanosome differentiation via transmission electron microscopy) on regenerating and newborn hair bulbs of Strain C57BL\6J wild-type agouti(AwJ/AwJ), lethal yellow (Ay/a), and nonagouti black (a/a) genotypes and 2) Northern and Western analyses of extrafollicular "target tissues" of the lYS (fat stores-obesity, ovarian follicles-infertility, pituicytes- potential MSH lesions, and splenocytes-immunosuppression); we plan to determine the chronology of agouti expression and assess whether Ay-induced pathologies in these tissues arise autonomously or by systemic action of agouti proteins made elsewhere. With respect to human health, experiments designed to correlate agouti expression with precise components of melanogenesis will provide refined information on how the agouti locus, one of about 50 genetic loci involved in the regulation of pigmentation, determines the balance of black, yellow, or both pigments within follicular melanocytes. An understanding of the agouti-encoded regulation of this "pigment equilibrium" (i.e., switch from black-to-yellow-to-black) should be productive for the diagnosis and treatment of melanomas an other pigment cell disorders, because we will possess a more fundamental knowledge of pigment cell metabolism and therefore a greater potential for drug intervention. Studies on aberrant LYS "target tissues" of adult Ay/a mice may allow us to identify molecular lesions common to those same conditions in humans -obesity, cancer, abnormal growth, compromised immunity, infertility, and diabetes resulting potentially in the development of new therapies. Because agouti expression apparently depends upon a signaling mechanism, we may discover that the common lesion uniting many of the pathologies of the LYS is a fundamental defect in cell signaling. Elucidation of the molecular bases of an Av- induced signaling lesion may yield important data on similar signaling lesions in humans.

我们广泛的长期目标是确定为什么鼠突变 agouti基因座，例如致命的黄色（AY）和可行的黄色（Avy）原因 致命黄色综合征（LYS）的病理学 - 肥胖，异常 色素沉着，癌症，增长增长，免疫抑制，不育和 糖尿病。 Agouti基因座调节色素类型（黑色和/或 黄色）合成的卵泡黑素细胞（Silvers，19790。Agouti） 等位基因改变特定的黑色素生成参数（Ito，1993； Tamate等，，， 1989; Granholm等，1990b）。 随着Agouti基因隔离的出现， 克隆，测序和部分特征（Bultman等，1992; Miller等，1993），我们现在第一次有机会 将黑色素发生的分子事件与几乎明确的分子事件相关联 Agouti表达的证据（即存在Agouti转录本 然后是合成Agouti蛋白）。 具体目的包括：1） 发展性北方分析以及特定测定 黑素生成（酪氨酸酶（酪氨酸羟化酶和DOPA氧化酶），酪氨酸酶）， 黑色素类型（总计，EU-和Phaeomelanin），Dopachrome Katomerse（DT）， 通过透射电子显微镜分化和黑色素体分化） 菌株C57BL \ 6J野生型野生型幼发鳞茎 Agouti（AWJ/AWJ），致命的黄色（AY/A）和Nonagouti Black（A/A）基因型 2）北部和西部分析外流体外“靶组织”的分析 Lys（脂肪店 - 肥胖，卵巢卵泡的可能性，pituicytes- 潜在的MSH病变和脾脏免疫抑制）；我们计划 确定Agouti表达的年表，并评估AY诱导的 这些组织中的病理是自主出现的，或者是通过全身作用 Agouti蛋白在其他地方生产的蛋白质。 关于人类健康，旨在与Agouti相关的实验 具有黑色素生成的精确成分的表达将提供精制 有关Agouti基因座的信息，该基因座是涉及的大约50个遗传基因座之一 在色素沉着的调节中，确定黑色，黄色的平衡 或两种卵泡黑素细胞中的颜料。 对 Agouti编码的“色素平衡”调节（即从 黑对黑对黑）应该对诊断和 治疗黑色素瘤的其他色素细胞疾病，因为我们将 对色素细胞代谢有更基本的了解和 因此，药物干预的潜力更大。 关于异常的研究 成年AY/A小鼠的LYS“靶组织”可能使我们能够鉴定分子 人类相同条件共有的病变 - 肥胖，癌症， 产生的异常生长，免疫力损害，不育和糖尿病 有可能发展新疗法。 因为agouti表达 显然取决于信号机制，我们可能会发现 共同病变将LYS的许多病理结合在一起是基本的 细胞信号的缺陷。 阐明AV-的分子碱基 诱导的信号病变可能会产生有关类似信号的重要数据 人类病变。