Compensatory Mechanisms Regulating Neuronal Fate Following Notch Signaling Perturbation

缺口信号扰动后调节神经元命运的补偿机制

• 批准号: 1257895
• 负责人: Margaret Saha
• 金额: $ 40万
• 依托单位: College of William and Mary
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2018-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1257895&HistoricalAwards=false
• 关键词: Compensatory; Mechanisms; Regulating; Neuronal; Fate

The process by which a sheet of undifferentiated cells within a developing embryo gives rise to a fully operational brain remains a pressing scientific problem with significant implications for understanding how brains function. Each neuron in the developing brain must adopt an appropriate cellular identity through a precise genetic program of spatial and temporal gene expression. Although these genetic programs do not always play out in an accurate manner, embryonic tissues have an enhanced ability to recover from perturbations as compared to adult tissues. The overall goal of this research is to identify the molecular mechanisms by which the embryonic nervous system responds to and recovers from these deviations from normal development. The experiments will employ a well-suited animal model system, namely the amphibian Xenopus laevis, that displays not only remarkable ability to compensate following genetic perturbation of the developmentally important Notch signaling pathway, but also employs a similar suite of genes to those regulating early human neural development. Using molecular, cellular and genetic tools, this research will uncover the specific genes and pathways that allow tissues to recover from genetic perturbation of Notch signaling. This will broaden our understanding of the ways in which the highly conserved Notch signaling pathway function to promote proper development of the nervous system in animals.Broader Impacts: This knowledge will contribute to understanding how and why processes go awry in human brain development and how these genetic pathways can potentially be manipulated in the emerging field of regenerative medicine. Equally importantly, the research will entail extensive undergraduate involvement in a manner that blends teaching and research; a cadre of undergraduate students, working with the principal investigator, will conduct the research as part of their science education and the experiments will also be incorporated into a new research-based genomics course. In order to engage the broader community, local teachers will have the opportunity to participate in the research through summer workshops.

在发育中的胚胎中，一组未分化的细胞产生一个完全运作的大脑的过程仍然是一个紧迫的科学问题，对理解大脑的功能具有重大意义。发育中的大脑中的每个神经元必须通过精确的空间和时间基因表达的遗传程序来采用适当的细胞身份。尽管这些遗传程序并不总是以准确的方式发挥作用，但与成年组织相比，胚胎组织从扰动中恢复的能力有所增强。这项研究的总体目标是确定胚胎神经系统对这些正常发育的偏差做出反应并从中恢复的分子机制。这些实验将使用一种非常适合的动物模型系统，即非洲爪哇两栖动物，它不仅显示出在发育重要的Notch信号通路的遗传扰动后具有非凡的补偿能力，而且还使用了一套与调节人类早期神经发育的基因相似的基因。利用分子、细胞和遗传工具，这项研究将揭示特定的基因和途径，使组织从Notch信号的遗传扰动中恢复过来。这将拓宽我们对高度保守的Notch信号通路促进动物神经系统正常发育的方式的理解。广泛的影响：这些知识将有助于理解人类大脑发育过程中如何以及为什么会出错，以及这些遗传途径如何可能在新兴的再生医学领域被操纵。同样重要的是，这项研究将需要本科生以一种将教学和研究相结合的方式进行广泛的参与；一批本科生干部将与首席研究员合作，将这项研究作为他们科学教育的一部分，这些实验也将被纳入一门新的以研究为基础的基因组学课程。为了让更广泛的社区参与，当地教师将有机会通过暑期讲习班参与研究。