Nutrient-dependent regulation of neural stem cell proliferation and neural circuit formation

神经干细胞增殖和神经回路形成的营养依赖性调节

• 批准号: 10206910
• 负责人: Sarah Elizabeth Siegrist
• 金额: $ 34.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206910
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adult; Affect; Alzheimer' s Disease; Animal Model; Behavior; Brain; Cell division; Cells; Complex; Consumption; Dependence; Development; Diet; Disease; Drosophila genus; Drosophila melanogaster; Genetic; Goals; Healthcare Systems; Human; Intrinsic factor; Learning; Location; Malignant Neoplasms; Maps; Memory; Microcephaly; Molecular; Morphology; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Nutrient; Pathway interactions; Population Heterogeneity; Research; Series; Societies; Specific qualifier value; Stem Cell Research; Techniques; Time; autism spectrum disorder; base; cell type; cost; dietary; insight; mature animal; nerve stem cell; neural circuit; neuroblast; neuroregulation; programs; response; single cell sequencing; stem cell proliferation; transcription factor

Our brain is composed of an immense diversity of neurons that are molecularly, morphologically, and functionally distinct. Understanding how this immense diversity of neuron types is generated and organized to allow us and other adult animals to carry out such a vast array of complex tasks and behaviors is of great importance. By far, most of the neurons in our adult brains are generated during development, either directly or indirectly from the cell divisions of a defined but, rather heterogeneous population of neural stem cells. Molecular differences exist among neural stem cells based on their location and neural stem cell themselves can change their intrinsic genetic programs over time. Research outlined in this proposal is geared towards better understanding of how neural stem cell extrinsic factors integrate with neural stem cell intrinsic factors to control numbers and types of neurons produced through time and space during development. In the Siegrist lab, we use the genetically tractable model organism, Drosophila melanogaster, to uncover the genetic pathways and molecular mechanisms regulating neural stem cell proliferation decisions, from quiescence to proliferation, and then termination once development is complete. Our research goals include gaining a better understanding of how dietary nutrient availability affects neural stem cell proliferation decisions. In Drosophila, different neural stem cells respond differently to dietary nutrient availability. Most enter and exit quiescence in a dietary nutrient- and PI3-kinase-dependent manner, except for a small subset. The neural stem cells that divide continuously independent of dietary nutrient availability are the neural stem cells that generate neurons important for memory and learning. Through genetic and single cell sequencing techniques, we are working to identify the intrinsic differences among these neural stem cell types that distinguish nutrient-dependence versus nutrient-independence. We are also working on determining how dietary nutrients consumed during development regulate neural stem cell temporal programs and thus types and numbers of neurons produced. Neural stem cells in Drosophila sequentially express a series of transcription factors over time that specify the neuron types produced at each cell division. Whether extrinsic factors, such as nutrient availability affects neuroblast intrinsic temporal programs is currently unknown. Finally, we are also working to map out the neural circuitry that regulates neural stem cell proliferation decisions in response to dietary nutrient availability. Altogether, the research outlined here will advance our understanding of neural stem cell proliferation control during development and how dietary nutrient availability affects types and numbers of neurons produced. These insights should stimulate new discoveries in translational stem cell research in the context of normal development and disease states.

我们的大脑由分子，形态学和 在功能上不同。了解如何生成和组织这种巨大的神经元类型的多样性 允许我们和其他成年动物执行如此庞大的复杂任务和行为非常出色 重要性。到目前为止，我们成年大脑中的大多数神经元是在开发过程中直接产生的，或者直接产生 间接从定义的细胞分裂，但是神经干细胞的异质种群。 神经干细胞之间的分子差异根据其位置和神经干细胞本身存在 可以随着时间的推移改变其内在的遗传程序。该提案中概述的研究旨在 更好地了解神经干细胞外在因素如何与神经干细胞的内在因素整合到 在发育过程中通过时间和空间产生的神经元的控制数和类型。 在Siegrist实验室中，我们使用遗传上的模型有机体，果蝇Melanogaster， 发现调节神经干细胞增殖决策的遗传途径和分子机制， 从静止到增殖，然后终止一旦发展完成。我们的研究目标 包括更好地了解饮食营养物的可用性如何影响神经干细胞的增殖 决定。在果蝇中，不同的神经干细胞对饮食营养的可用性有所不同。最多 以饮食中的营养和PI3-激酶依赖性方式输入和出口静止，除了小子集外。 神经干细胞连续分开独立于饮食营养的可用性是神经茎 产生神经元对于记忆和学习很重要的细胞。通过遗传和单细胞测序 技术，我们正在努力确定这些神经干细胞类型之间的内在差异 区分营养素依赖性与营养独立性。我们还在努力确定如何 发育过程中消耗的饮食营养素调节神经干细胞时间程序，因此类型 和产生的神经元数量。果蝇中的神经干细胞顺序表达一系列 转录因子随着时间的推移指定了每个细胞分裂产生的神经元类型。是否外部 目前尚不清楚诸如养分可用性之类的因素，会影响神经细胞内在的时间程序。 最后，我们还努力绘制调节神经干细胞增殖的神经回路 响应饮食营养物的可用性的决定。总之，这里概述的研究将推动我们的 了解开发过程中神经干细胞增殖的控制以及饮食中的养分如何 影响产生的神经元的类型和数量。这些见解应刺激新发现 在正常发育和疾病状态的背景下，转化干细胞研究。