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: 10798923
• 负责人: Sarah Elizabeth Siegrist
• 金额: $ 9.58万
• 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/10798923
• 关键词: Adult; Affect; Alzheimer' s Disease; 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; Nutrient availability; PIK3CG gene; Pathway interactions; Population Heterogeneity; Proliferating; Research; Series; Societies; Specific qualifier value; Stem Cell Research; Techniques; Time; autism spectrum disorder; cell type; cost; dietary; insight; mature animal; model organism; nerve stem cell; neural circuit; neuroblast; neuroregulation; programs; response; single cell sequencing; stem cell proliferation; transcription factor

Project Summary/Abstract: 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 cells 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, affect 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.

项目摘要/摘要： 我们的大脑由分子，形态学和 在功能上不同。了解如何产生这种神经元类型的多样性以及 组织以允许我们和其他成年动物执行如此庞大的复杂任务和 行为非常重要。到目前为止，我们成人大脑中的大多数神经元是在 开发，直接或间接地从定义但相当异质的细胞分裂中 神经干细胞的种群。神经干细胞之间存在分子差异 位置和神经干细胞本身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理解神经干细胞的方式 外在因素与神经干细胞的内在因子整合以控制神经元数量和类型 在开发过程中通过时间和空间生产。 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的遗传途径和分子机制 从静止到增殖的决策，然后一旦开发完成后终止。我们的 研究目标包括更好地了解饮食营养的可用性如何影响神经 干细胞增殖决策。在果蝇中，不同的神经干细胞对饮食的反应不同 营养可用性。大多数在饮食营养和PI3-激酶依赖的饮食中进入和退出静止 方式，除了一个小子集。神经干细胞连续划分与饮食无关 营养可用性是产生对记忆和学习重要的神经元的神经干细胞。 通过遗传和单细胞测序技术，我们正在努力识别固有的 这些神经干细胞类型之间的差异，这些神经干细胞类型区分营养素依赖性与养分 独立。我们还在努力确定饮食营养在 开发调节神经干细胞时间程序，从而调节神经元的类型和数量 生产。果蝇中的神经干细胞随时间顺序表达一系列转录因子 该指定在每个细胞分裂中产生的神经元类型。外在因素（例如养分）是否 目前尚不清楚可用性，影响神经细胞内在的时间程序。最后，我们也是 努力绘制调节神经干细胞增殖决策的神经回路 对饮食养分的反应。总之，这里概述的研究将推动我们的 了解发育过程中神经干细胞增殖的控制以及饮食中的营养如何 可用性会影响产生的神经元的类型和数量。这些见解应刺激新的 在正常发育和疾病状态的背景下，转化干细胞研究中的发现。