The role of melanocyte precursors in zebrafish pigmentation disorders

黑素细胞前体在斑马鱼色素沉着疾病中的作用

• 批准号: 8207200
• 负责人: Richard Mark White
• 金额: $ 3.36万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8207200
• 关键词: Address; Adult; BRAF gene; Basic Science; Biology; Cells; Characteristics; Chemicals; Clinical; Clinical Research; Data; Defect; Development; Disease; Embryo; Embryonic Development; Endothelin; Endothelin Receptor; Endothelin Receptor Antagonist; Engraftment; Ensure; Enzyme Inhibition; Event; Fishes; Future; Gene Expression; Genes; Genetic; Goals; Growth; Hour; Human; Hypopigmentation; In Situ Hybridization; Informatics; Lead; Libraries; Life; Ligands; Link; Mole the mammal; Mutate; Neural Crest; Nevi and Melanomas; Oncogenes; Pathway interactions; Patients; Pattern; Penetrance; Pharmaceutical Preparations; Phenotype; Physicians; Pigmentation Disorders; Pigmentation physiologic function; Pigments; Population; Proliferating; Research Personnel; Research Training; Resources; Role; Scientist; Screening procedure; Signal Pathway; Signal Transduction; Structure; System; Testing; Therapeutic; Transgenic Organisms; Transplantation; Vitiligo; Zebrafish; base; career; chemical genetics; endothelin-converting enzyme; human disease; insight; mature animal; melanocyte; melanoma; mutant; novel; overexpression; prevent; progenitor; programs; promoter; research study; small molecule; tool; tumor

DESCRIPTION (provided by applicant): My clinical and research training has long been geared towards a career as a physician-scientist who is able to bridge the gap between clinical observations and basic science approaches to these problems. This application is a critical part of my growth in this regard, and will ensure that I have the resources necessary to achieve this goal. PROJECT SUMMARY: Disorders of pigmented melanocytes are responsible for a number of human diseases, from the hypopigmentation of vitiligo to the fatal consequences of malignant melanoma. Understanding the genetic pathways that are involved in the development of the neural crest and its derivatives, including melanocytes, is a critical component of treating diseases of these lineages. In this proposal, I plan to use the zebrafish to understand how perturbations in the normal development of embryonic neural crest and melanocyte precursors is related to adult pigmentation disease such as nevi and melanoma. We have developed transgenic BRAF;p53 mutant fish that are morphologically normal as embryos yet have severe pigmentation disruption and melanoma as adults. Gene expression analyses demonstrates a conserved gene signature between BRAF;p53 embryos and tumors, suggesting a link between events early in embryogenesis and tumor formation. In Specific Aim 1,1 have utilized this information as the basis of a chemical screen to identify pathways and molecules that are relevant to preventing initiating events in melanoma formation. Hits which emerge from this screen are tested for their ability to alter the adult BRAF;p53 phenotype. Preliminary data of one hit, MLT013, demonstrates that it inhibits pigment stripe disruption as well as melanoma transplantability. MLT013 likely functions through endothelin receptor blockade. In Aim 2,1 describe experiments which determine whether endothelins cooperate with BRAF to drive melanoma formation. These studies aim to uncover novel signaling pathways that will provide the rationale for future studies as an independent investigator, and may offer therapeutic benefit to patients with nevi and melanoma. LAY SUMMARY: Our current understanding of diseases related to pigmentation, such as moles and melanoma, is limited. The zebrafish has yielded important insights into the biology of these diseases, and I plan to study this fish as a tool for identifying new pathways and drugs for the treatment of these human diseases.

描述（由申请人提供）：我的临床和研究培训长期以来一直致力于作为医生 - 科学家的职业，他能够弥合临床观察和基础科学方法之间解决这些问题的差距。该应用程序是我在这方面增长的关键部分，并将确保我拥有实现这一目标所需的资源。项目摘要：色素黑素细胞的疾病是导致多种人类疾病的原因，从白癜风的不形成到恶性黑色素瘤的致命后果。了解神经rest及其衍生物（包括黑素细胞）的遗传途径是治疗这些谱系疾病的关键组成部分。在此提案中，我计划使用斑马鱼来了解胚胎神经rest和黑色素细胞前体的正常发育中的扰动与成人色素沉着疾病（如Nevi和黑色素瘤）有关。我们已经开发了转基因BRAF; p53突变鱼在形态上正常，但作为胚胎却有严重的色素沉着破坏和黑色素瘤。基因表达分析表明，BRAF; p53胚胎和肿瘤之间存在一个保守的基因特征，这表明胚胎发生早期事件与肿瘤形成之间存在联系。在特定目标中，1,1利用这些信息作为化学筛选的基础，以识别与防止黑色素瘤形成中引发事件相关的途径和分子。从此屏幕中出现的命中率有其改变成年BRAF; p53表型的能力。一个命中的初步数据MLT013表明，它抑制了色素条纹的破坏以及黑色素瘤的移植性。 MLT013可能通过内皮素受体阻断发挥作用。在AIM 2,1中描述了确定内皮素是否与BRAF合作以驱动黑色素瘤形成的实验。这些研究旨在发现新颖的信号通路，这将为将来作为独立研究者提供基本原理，并可能为NEVI和黑色素瘤患者提供治疗益处。摘要：我们目前对与色素沉着有关的疾病（例如痣和黑色素瘤）的理解是有限的。斑马鱼对这些疾病的生物学产生了重要的见解，我计划研究这种鱼作为识别治疗这些人类疾病的新途径和药物的工具。