Melanocyte boundary interactions in development and neoplasia

发育和肿瘤形成中黑素细胞边界的相互作用

• 批准号: 8075202
• 负责人: DAVID M PARICHY
• 金额: $ 38.81万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8075202
• 关键词: Ablation; Adult; Affect; Animals; Behavior; Biological; Cell Communication; Cell Differentiation process; Cell Maintenance; Cell Separation; Cells; Data; Defect; Development; Disease; Embryo; Embryonic Development; Environment; Event; Failure; Gene Expression Profile; Genes; Genetic; Goals; Growth; Health; Hereditary Disease; Homeostasis; Human; Image; In Situ Hybridization; Injury; Knowledge; Light; Logic; Maintenance; Malignant Neoplasms; Mediating; Melanoma Cell; Methods; Molecular; Morphogenesis; Mutation; Natural regeneration; Neoplasm Metastasis; Neoplasms; Organism; Organogenesis; Pathway interactions; Pattern; Pattern Formation; Phenotype; Pigments; Population; Potassium Channel; Process; Reporter; Research; Research Personnel; Role; Series; Spottings; Staging; Testing; Time; Tissue Engineering; Tissues; Variant; Zebrafish; base; cell behavior; cell transformation; critical period; insight; interest; melanocyte; melanoma; mutant; neoplastic; nexin; novel; practical application; regenerative; response; tissue regeneration

DESCRIPTION (provided by investigator): The establishment of boundaries between cells and tissues is a critical feature of pattern forma- tion in every animal embryo. These same boundaries must be maintained and new ones established as organogenesis and growth continue during later post-embryonic development. Still later in the adult, the maintenance of cell and tissue boundaries is essential for normal homeo- stasis. The mechanisms underlying such boundaries are thus of fundamental biological significance. Yet these same mechanisms also have profound implications for a variety of genetic diseases, cancers, in which boundary constraints are lost, and regenerative contexts, in which boundaries must be formed anew. The goal of this project is to understand the genetic and cellular mechanisms underlying cellular boundaries in post-embryonic vertebrate development. To this end, these studies will employ an especially tractable example of boundary formation, the development and maintenance of adult pigment stripes in the zebrafish. Previous efforts demonstrated that interactions between different classes of pigment cells are essential for normal stripes to develop, though the genes and cell behaviors involved have yet to be elucidated. In proposed Aim 1, time-lapse imaging will be used to visualize cell-cell interactions during stripe development and regeneration, and to test the hypothesis that direct, short-range and long- range contacts are involved. Aim 2 will test functions of previously isolated and new genes for which mutants have boundary-defective phenotypes. In addition to normal development, these studies will extent to imaging the behavior of melanoma cells and how invasion and metastasis by these cells is affected by genetic background. Aim 3 will build upon earlier studies by testing a new class of pigment cell for its function in boundary formation, as well as the role of a candidate genetic pathway for mediating these effects. Finally, Aim 4 will identify new genes and pathways contributing to stripe boundary formation through the analysis of candidate pathways as well as comparisons of whole transcriptomes between defined pigment cell populations across stages and genetic backgrounds. These studies will provide valuable new insights into the genetics of pigment cell boundary formation and melanoma progression, as well as the logic of boundary forming mechanisms more generally. PUBLIC HEALTH RELEVANCE: The establishment and maintenance of cell and tissue boundaries is critical for normal development. In turn, discovering the mechanisms underlying such processes will have important implications for human health and disease, as well as efforts to stimulate tissue regeneration following traumatic injury. These studies in this proposal focus on pigment cells, which in humans are associated with a variety of disorders including melanoma. Our research will shed new light on the genes and cell behaviors responsible for the formation and maintenance of boundaries during development, and how these mechanisms interact with the neoplastic state.

描述（研究人员提供）：细胞和组织之间的边界是每个动物胚胎中模式形成的关键特征。这些相同的界限必须维护，并确定新的边界，因为在后来的胚胎后发育期间，器官发生和生长仍在继续。在成年人的晚些时候，维持细胞和组织边界对于正常同源性是必不可少的。因此，这种边界的基础机制具有基本的生物学意义。然而，这些相同的机制也对各种遗传疾病，癌症和边界约束丢失和再生环境具有深远的影响，其中必须重新形成边界。该项目的目的是了解胚后脊椎动物发育中细胞边界的遗传和细胞机制。为此，这些研究将采用一个特别典型的边界形成的例子，斑马鱼中成年色素条纹的发展和维护。先前的努力表明，不同类别的色素细胞之间的相互作用对于正常条纹的发展至关重要，尽管涉及的基因和细胞行为尚未阐明。在拟议的AIM 1中，将使用延时成像来可视化条纹发展和再生过程中的细胞 - 细胞相互作用，并测试涉及直接，短距离和长距离接触的假设。 AIM 2将测试突变体具有边界缺陷表型的先前分离和新基因的功能。除了正常发育外，这些研究还将有助于成像黑色素瘤细胞的行为以及这些细胞的侵袭和转移如何受遗传背景的影响。 AIM 3将通过测试一类新的色素细胞在边界形成中的功能以及候选遗传途径介导这些作用的作用来基于早期的研究。最后，AIM 4将通过分析候选途径的分析来确定有助于条纹边界形成的新基因和途径，以及在跨阶段和遗传背景之间定义的色素细胞群体之间整个转录组之间的比较。这些研究将为色素细胞边界形成和黑色素瘤进展的遗传学以及边界形成机制的逻辑提供宝贵的新见解。 公共卫生相关性：细胞和组织边界的建立和维护对于正常发展至关重要。反过来，发现此类过程的基础机制将对人类健康和疾病产生重要影响，以及刺激创伤性损伤后组织再生的努力。该提案中的这些研究集中在色素细胞上，在人类中，这些细胞与包括黑色素瘤在内的多种疾病有关。我们的研究将对导致开发过程中边界形成和维持的基因和细胞行为进行新的启示，以及这些机制如何与肿瘤状态相互作用。