Proliferative asymmetry in the neural stem cell lineage established by asymmetric cell division
由不对称细胞分裂建立的神经干细胞谱系的增殖不对称性
基本信息
- 批准号:10664431
- 负责人:
- 金额:$ 12.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-07 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:Animal ModelAnimalsApicalBiological AssayBrainCell CycleCell LineageCell ProliferationCell divisionCellsCentral Nervous SystemDataDaughterDefectDevelopmentDiseaseDrosophila genusEducational process of instructingEnsureFailureGoalsGrantGrowthInheritedInvertebratesLaboratoriesLearningLipidsMeasuresMediatingMentorsModelingMolecularMothersNeuronsOrganPIK3CG genePathway interactionsProliferatingProliferation MarkerProteinsRegulationResearchRoleRunningS-Phase FractionSiblingsSideSpecific qualifier valueSystemTestingTissuesTrainingTraining ActivityVertebratesWorkWritingZebrafishcell cortexcell typedaughter cellfollow-upimprovedlive cell imagingmembernerve stem cellneurogenesispreventprogramsrepairedscreeningsegregationskillsstem cell divisionstem cell proliferationstem cell therapystem cellstissue repairtraining opportunitytumorigenesis
项目摘要
ABSTRACT
In the proposed work, I will be investigating how neural stem cells establish ‘proliferative asymmetries’, which
are responsible for precisely controlling the development and repair of the central nervous system. During
development and tissue repair, stem cells are triggered to proliferate. While proliferation is necessary, it must be
precise to prevent overgrowth that can lead to tumorigenesis. As neural stem cells proliferate, they commonly
divide asymmetrically. The ability to undergo asymmetric cell division is a highly conserved feature of neural
stem cells across all animals. Asymmetric cell division produces one daughter cell that retains the neural stem
cell identity, and one daughter cell which takes on a neuron-producing progenitor cell identity. A key difference
between these two daughter cells is that the stem cell will rapidly reenter the cell cycle and divide again, while
the progenitor cell will divide much more slowly or stop dividing all together. This proliferative asymmetry ensures
that the proper number of neurons are produced, and its disruption leads to defects in neurogenesis. The
molecular basis for this proliferative asymmetry mostly unknown. I will focus my independent research program
around the mechanisms which establish this proliferative asymmetry. I hypothesize that this proliferative
asymmetry is established by the differential inheritance of proliferation promoting factors during asymmetric cell
division. I plan to learn how neural stem cells generate proliferative asymmetries in both invertebrates and
vertebrates, through the use of Drosophila and zebrafish animal models. Studying both animal models will allow
me to identify conserved and divergent modes of generating proliferative asymmetries in neural stem cells, while
also providing me with new training opportunities. Both animal models are highly amenable to live cell imaging
of neural stem cells in developing brains. In Aim 1, I will screening for proliferation regulators which are polarized
in the mother neural stem cell. In Aim 2, I will determine how polarized proliferative regulators contribute to
proliferative asymmetries between sibling cells. In Aim 3, I will determine how PAR polarity proteins regulate the
PI3K proliferation pathway. Through my initial screening, I have already discovered one promising candidate
that appears to mediate the proliferative asymmetry in the neural stem cell lineage, the lipid PIP3. PIP3 is
transiently produced by the mother neural stem cell just before division, becomes polarized to one side of the
cell, and gets inherited by the daughter cell which retains the neural stem cell identity. Discovering how PIP3
and other factors establish proliferative asymmetries during asymmetric cell division will advance our
understanding of how neural stem cells mediate development and tissue repair. Through training activities aimed
at improving my skills in grant writing, scientific teaching, and mentoring, I will be better prepared to run my own
laboratory. The scientific discoveries and training this proposal will facilitate, will be foundational to building my
independent research program.
摘要
在拟议的工作中,我将研究神经干细胞如何建立“增殖不对称性”,即
负责精确控制中枢神经系统的发育和修复。期间
在干细胞的发育和组织修复过程中,干细胞被触发增殖。虽然扩散是必要的,但必须
精确地防止可能导致肿瘤发生的过度生长。当神经干细胞增殖时,它们通常
不对称地划分。经历不对称细胞分裂的能力是神经细胞的高度保守特征
所有动物的干细胞。不对称的细胞分裂产生一个保留神经干的子细胞
细胞身份,以及一个具有神经元产生祖细胞身份的子细胞。一个关键区别
这两个子细胞之间的区别是干细胞将迅速重新进入细胞周期并再次分裂,而
祖细胞将分裂得慢得多或完全停止分裂。这种增殖性的不对称性确保了
正常数量的神经元被产生,而它的破坏导致神经发生的缺陷。的
这种增生性不对称的分子基础大多未知。我会专注于我的独立研究项目
建立这种增殖性不对称的机制。我假设这种增殖性的
不对称性是通过不对称细胞增殖过程中增殖促进因子的差异遗传建立的。
师.我计划研究神经干细胞如何在无脊椎动物和
脊椎动物,通过使用果蝇和斑马鱼动物模型。研究这两种动物模型将使
我确定保守和不同的模式产生增殖不对称的神经干细胞,而
也给我提供了新的培训机会。这两种动物模型都非常适合活细胞成像
神经干细胞在发育中的大脑中的作用。在目标1中,我将筛选极化的增殖调节因子,
在母体神经干细胞中。在目标2中,我将确定极化增殖调节因子如何促进
兄弟细胞之间的不对称性。在目标3中,我将确定PAR极性蛋白如何调节
PI3K增殖途径。通过初步筛选,我已经发现了一个有希望的候选人
它似乎介导了神经干细胞谱系中的增殖不对称性,脂质PIP3。PIP3是
由母体神经干细胞在分裂前短暂产生,向一侧极化。
神经干细胞是神经干细胞的一部分,它是神经干细胞的一部分。了解PIP3
和其他因素在不对称细胞分裂过程中建立增殖不对称性将促进我们的
了解神经干细胞如何介导发育和组织修复。通过旨在
通过提高我在撰写资助申请、科学教学和指导方面的技能,我将更好地准备自己的事业。
实验室科学发现和培训这一建议将促进,将是基础建设我的
独立研究计划。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bryce LaFoya其他文献
Bryce LaFoya的其他文献
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{{ truncateString('Bryce LaFoya', 18)}}的其他基金
Membrane Localization of Atypical Protein Kinase C during Neuroblast Polarization
神经母细胞极化过程中非典型蛋白激酶 C 的膜定位
- 批准号:
10001981 - 财政年份:2019
- 资助金额:
$ 12.5万 - 项目类别:
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