Neural Crest Ontogeny and the Control of Stem Cell Attributes

 描述（由申请人提供）：神经嵴细胞（NC细胞）是建立脊椎动物身体计划所必需的，提供了许多关键细胞类型。了解控制这些细胞形成和发育的分子机制对于了解先天性缺陷和再生医学具有重要意义。此外，该提案所关注的几种蛋白质与肿瘤起始细胞（又名癌症干细胞）和转移的形成有明确和确定的联系。通过进一步阐明这些蛋白质调节NC和多能囊胚/ES细胞正常发育的机制，我们将进一步了解它们在NC衍生肿瘤中的作用，以及更普遍的干细胞、恶性转化和侵袭性细胞行为。我们以前已经确定了NC细胞潜能的潜在因素，包括Myc和Id 3。这里提出的工作是潜在的范式转变，因为它提出和测试一个新的假设NC细胞的起源和它们的关系，多能囊胚/内细胞团细胞。我们建议，一个监管网络支持多能性的囊胚外胚层至少部分地保留在选择细胞通过原肠胚形成，并通过神经胚阶段，这些细胞位于神经板的边界，并成为NC细胞凭借其保留的效力。我们还剖析了关键效力因子的调控靶点，并检验了以下假设：NC、ES和癌症干细胞的关键调控因子Snail蛋白是激活和抑制关键靶基因的背景依赖性因子。提出的目标将大大推进我们对一种重要细胞类型的理解，并提供一个新的框架来理解它们的起源和干细胞属性。这项工作有很大的潜力，以推动新的方法，以干细胞为基础的治疗，以及癌症诊断/治疗

 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