The Fate of Epidermal Melanocytes

表皮黑素细胞的命运

• 批准号: 7059465
• 负责人: Kelly McGowan
• 金额: $ 10.09万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059465
• 关键词: apoptosis; cell differentiation; cell migration; cell population study; developmental genetics; gene induction /repression; gene mutation; genetic mapping; hair; hair follicle; laboratory mouse; melanocyte; pigmentation; skin; tissue mosaicism

DESCRIPTION (provided by applicant): Variation in human skin color is mediated by changes in the activity of epidermal melanocytes, while hair color is determined by the action of melanocytes located in the hair follicle. To date, few genes and pathways have been identified that control a melanocytes decision to adopt an inter-follicular or an extra-follicular fate. Understanding the origins of these two melanocyte subpopulations, and identifying molecules and pathways that may be involved in melanocyte specification may have implications for the treatment of human conditions that specifically affect each subset of cells. To understand the origins of these two melanocyte subpopulations, two complementary approaches are outlined in this proposal. First, using genetic tools that take advantage of site-specific recombination, the fate of melanocyte precursors in wild type mice will be analyzed. Analysis of mosaic animals will be performed to determine if inter-follicular and extrafollicular melanocytes arise from distinct lineages or from a common precursor pool. Second, our laboratory has initiated a project to study a new class of mouse pigmentation mutants that were identified by their dark skin (Dsk) phenotype. We have determined the genetic map location, homozygous phenotype and histologic determinants of ten dominant Dsk mutants, and have identified one class of Dsk mutants, represented by Dsk3, Dsk4, and Dsk6, that has increased epidermal pigment in non-hairy skin. In subsequent studies, we have found that Dsk3 animals have an increased number of epidermal melanocytes in the tail and the footpad, and a reduced number of follicular melanocytes. Dsk4 and Dsk6 animals, on the other hand, have dark skin based on mechanisms independent of pigment cell number. The expansion of the pigment cell population in Dsk3 adult animals may be due to an increase in the number of melanocyte precursors, aberrant melanocyte migration, an increase in cell proliferation or a decrease in programmed cell death. The mechanism by which Dsk3 causes an increased number of epidermal melanocytes will be investigated. In addition, the gene responsible for the dark skin phenotype in Dsk3 mutants will be identified, and the nature of the mutation explored. In future efforts, the mechanisms that control dark skin in Dsk4 and Dsk6 animals will be investigated. Studies of dark skin mutant mice may provide insight into the mechanisms by which epidermal melanocytes choose to contribute to hair color (an intra-follicular fate) or skin color {and extra-follicular fate). This body of work and the proposed career development plan combine my interests in dermatology, cutaneous biology and genetics, and will serve as a springboard from which I will be able to develop an independent research program in a university setting. The support of the Mentored Clinical Scientist Development Award (K08) and the guidance of Dr. Greg Barsh (mentor for this proposal) will facilitate the transition from a mentored trainee to a junior faculty position.

描述（由申请人提供）：人类肤色的变化是由表皮黑素细胞活性的变化介导的，而头发颜色是由位于毛囊中的黑素细胞的作用确定的。迄今为止，很少有基因和途径能够控制黑素细胞决定采用狂热间或狂热外命运。了解这两种黑素细胞亚群的起源，并鉴定可能与黑素细胞规范有关的分子和途径可能对治疗人类条件的治疗有影响，该治疗特异性地影响了细胞的每个子集。为了了解这两种黑素细胞亚群的起源，该提案中概述了两种互补的方法。 首先，使用利用位点特异性重组的遗传工具，将分析野生型小鼠中黑素细胞前体的命运。将对镶嵌动物进行分析，以确定是由不同的谱系或共同的前体池引起的洋腹和毛囊外黑素细胞。其次，我们的实验室启动了一个项目，以研究新的小鼠色素沉着突变体，这些突变体被其深色皮肤（DSK）表型鉴定出来。我们已经确定了十种主要的DSK突变体的遗传图位置，纯合表型和组织学决定因素，并确定了由DSK3，DSK4和DSK6代表的一类DSK突变体，这些突变体在非伴随皮肤中增加了表皮色素。在随后的研究中，我们发现DSK3动物在尾巴和脚下的表皮黑素细胞数量增加，并且卵泡黑素细胞数量减少。另一方面，DSK4和DSK6动物具有深色皮肤，基于与色素细胞数的机制。 DSK3成年动物中色素细胞种群的扩展可能是由于黑素细胞前体的数量增加，异常黑色素细胞迁移，细胞增殖增加或程序性细胞死亡的减少。 DSK3导致表皮黑素细胞数量增加的机制将被研究。另外，还将鉴定出负责DSK3突变体中深色皮肤表型的基因，并探讨了突变的性质。在将来的努力中，将研究控制DSK4和DSK6动物中深色皮肤的机制。深色皮肤突变小鼠的研究可能会深入了解表皮黑素细胞选择对头发颜色有助于（狂热内命运）或肤色（和炎热命运）的机制。 这项工作和拟议的职业发展计划将我对皮肤病学，皮肤生物学和遗传学的兴趣结合在一起，并将作为跳板，我将能够从中开发一个独立的研究计划。受过指导的临床科学家发展奖（K08）的支持以及格雷格·巴什（Greg Barsh）博士（该提案的导师）的指导将有助于从受过导师的学员到初级教师职位的过渡。