Neural Crest Ontogeny and the Control of Stem Cell Attributes

 描述(申请人提供)：神经脊细胞(NC细胞)对于建立脊椎动物的身体计划是必不可少的，贡献了许多关键的细胞类型。了解控制这些细胞形成和发育的分子机制对于了解先天缺陷和再生医学具有重要意义。此外，这一提议的中心所在的几种蛋白质与肿瘤起始细胞(又名癌症干细胞)的形成和转移有明确和确定的联系。通过进一步阐明这些蛋白调控NC和多能胚泡/ES细胞正常发育的机制，我们将进一步深入了解它们在NC来源的肿瘤中的作用，以及更广泛的干细胞分化、恶性转化和侵袭性细胞行为。我们之前已经确定了NC细胞潜能的潜在因素，包括Myc和ID3。这里提出的工作是潜在的范式转换，因为它提出并测试了关于NC细胞的起源及其与多能囊胚/内细胞团细胞的关系的新假说。我们认为，胚泡外胚层中支持多能性的调控网络至少部分地通过原肠发育保留在选定的细胞中，到神经胚期，这些细胞位于神经板边缘，并凭借其保留的能力成为NC细胞。我们还剖析了关键效力因子的调控靶点，并检验了Snail蛋白是NC、ES和癌症干细胞的关键调节因子是激活和抑制关键靶标基因的上下文依赖因子的假设。提出的目标将大大促进我们对一种重要细胞类型的理解，并提供一个新的框架，用来理解它们的起源和干细胞属性。这项工作有很高的潜力推动干细胞基础疗法以及癌症诊断/治疗的新方法。

 DESCRIPTION (provided by applicant): Neural crest cells (NC cells) are essential to establishing the vertebrate body plan, contributing many critical cell types. Understanding the molecular mechanisms that control the formation and development of these cells is of high importance to understanding congenital defects, and for regenerative medicine. Moreover, several of the proteins upon which this proposal centers have clear and established links to the formation of tumor initiating cells (aka Cancer Stem Cells) and metastasis. By further elucidating the mechanisms by which these proteins regulate the normal development of NC and pluripotent blastula/ES cells, we will gain further insight into their role in NC derived tumors, ad in stemness, malignant transformation and invasive cell behavior more generally. We have previously identified factors underlying NC cell potency, including Myc and Id3. The work proposed here is potentially paradigm shifting as it presents and tests a novel hypothesis for the origins of NC cells and their relationship to pluripotent blastula/inner cell mass cells. We propose that a regulatory network supporting pluripotency in the blastula ectoderm is at least partially retained in select cells through gastrulation, and by neurula stage these cells are located at the neural plate border, and become NC cells by virtue of their retained potency. We also dissect regulatory targets of key potency factors, and test the hypothesis that Snail proteins, key regulators of NC, ES and cancer stem cells, are context dependent factors that both activate and repress key target genes. The proposed aims will significantly advance our understanding of an important cell type, and provide a new framework with which to understand their origins and stem cell attributes. This work has high potential to drive novel approaches to stem cell bases therapies, as well as cancer diagnostics/ therapeutics