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: 10442438
• 负责人: Sarah Elizabeth Siegrist
• 金额: $ 39.71万
• 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/10442438
• 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.

我们的大脑是由各种各样的神经元组成的，这些神经元在分子上，形态上， 功能不同。了解神经元类型的巨大多样性是如何产生和组织的， 让我们和其他成年动物能够执行如此广泛的复杂任务和行为是非常重要的 重要性到目前为止，我们成年人大脑中的大多数神经元都是在发育过程中产生的，要么直接产生，要么直接产生。 间接来自于一个确定的，但相当异质的神经干细胞群体的细胞分裂。 神经干细胞之间存在着分子差异，这取决于神经干细胞的位置和神经干细胞本身 可以随着时间的推移改变它们内在的遗传程序。本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内在因素整合， 控制神经元的数量和类型在发育过程中通过时间和空间产生。 在Siegrist实验室，我们使用遗传学上易于处理的模式生物，黑腹果蝇， 揭示调节神经干细胞增殖决定的遗传途径和分子机制， 从静止到增殖，然后一旦发育完成就终止。我们的研究目标 包括更好地了解膳食营养素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膳食营养素的可用性有不同的反应。最 进入和退出静止在饮食营养和PI3激酶依赖性的方式，除了一个小的子集。 神经干细胞的分裂不依赖于膳食营养素的供应， 这些细胞产生对记忆和学习很重要的神经元。通过基因和单细胞测序 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， 区分营养依赖和营养独立。我们也在研究如何 在发育过程中消耗的膳食营养素调节神经干细胞的时间程序， 和产生的神经元数量。果蝇的神经干细胞依次表达一系列 随着时间的推移，这些转录因子指定了每次细胞分裂时产生的神经元类型。无论是外在的 因素，如营养的可用性影响神经母细胞内在的时间程序是目前未知的。 最后，我们还在努力绘制出调节神经干细胞增殖的神经回路 决定对膳食营养素的可用性。总之，这里概述的研究将推动我们的 了解发育过程中的神经干细胞增殖控制以及膳食营养素的可用性 影响神经元的种类和数量这些见解应该会激发新的发现， 在正常发育和疾病状态下的转化干细胞研究。