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RUI: Adult neurogenesis: Contributions from the innate immune system

RUI：成人神经发生：先天免疫系统的贡献

基本信息

批准号：
1656103
负责人：
Barbara Beltz
金额：
$ 60万
依托单位：
Wellesley College
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656103&HistoricalAwards=false
关键词：
RUI Adult neurogenesis Contributions innate

项目摘要

This project examines the role that the immune system plays in the production of new cells (neurons) in the adult brain. Adult crayfish are used for this research because the cell populations that produce new neurons are much easier to study and manipulate than in other animals commonly used for this type of research. Unlike neural stem cells in other animals such as mice, the population of cells that directly produces new neurons in adult brains do not self-renew; rather, this population appears to be replenished by cells coming from some other source in the body. Previous data indicate that the immune system provides these precursor cells to the adult crayfish brain. The goal of this proposal is to build on this previous research to definitively identify how the immune system contributes to the generation of adult-born neurons. The experiments are designed to test three hypotheses. The first aim examines the hypothesis that circulating blood/immune cells (hemocytes) interact with specific physical locations in the crayfish brain (neurogenic niches), that cause these cells to remain and produce descendants that differentiate into neurons. The second aim examines the hypothesis that hemocytes are chemically attracted to the neurogenic niches by specific molecules. The third aim examines the hypothesis that the nervous system regulates the production of the neural precursors by the immune system via the release of a chemical (serotonin) that biochemically modulates the fate of immune system cells. By clearly identifying these cellular and molecular influences, these studies will contribute to fundamental knowledge about how stem cells enable the production of new neurons in adult brains. This work also contributes to society through training undergraduates in stem cell research, and educating the general public about the value of non-mammalian biological research and the potential for life-long plasticity in the nervous system.In this project, GFP-positive (GFP+) hemocytes originating in transgenic crayfish will be adoptively transferred to recipient non-transgenic animals, and their target organs and differentiated properties will be determined. In addition, GFP+ cells extracted from different regions of the immune system in transgenic crayfish will be used in adoptive transfers to define the tissue origins of cells that are competent to produce adult-born neurons. These studies will also identify local guidance cues that attract hemocytes to the neurogenic niche using in vitro cell migration assays, as well as in situ nucleic acid hybridization and immunocytochemistry to locate candidate molecules that have been identified by transcriptome analyses. Finally, the coordinated regulation of the innate immune system and adult neurogenesis by a 5-HT-activated cytokine (astakine 1; AST1) pathway will be tested. Differential expression and localization of AST1 in niche, brain and immune tissues will be assessed after altering 5-HT levels. By testing the hypothesis that cells originating in the innate immune system produce adult-born neurons, these studies challenge the canonical view that the ectodermal origins of embryonic neural tissues are the sole source of neurons in the adult brain.

该项目研究免疫系统在成人大脑中产生新细胞（神经元）中的作用。成年小龙虾被用于这项研究，因为产生新神经元的细胞群比通常用于这类研究的其他动物更容易研究和操纵。与小鼠等其他动物的神经干细胞不同，成年大脑中直接产生新神经元的细胞群不会自我更新;相反，这个细胞群似乎是由来自体内其他来源的细胞补充的。先前的数据表明，免疫系统为成年小龙虾的大脑提供了这些前体细胞。该提案的目标是建立在以前的研究基础上，以明确确定免疫系统如何有助于成年出生的神经元的产生。实验旨在验证三个假设。第一个目的是检验循环血液/免疫细胞（血细胞）与小龙虾大脑（神经源性壁龛）中的特定物理位置相互作用的假设，这导致这些细胞保留并产生分化为神经元的后代。第二个目的是检验血细胞被特定分子化学吸引到神经原性龛的假设。第三个目的是检验神经系统通过释放一种化学物质（血清素）来调节免疫系统神经前体的产生的假设，该化学物质以生物化学方式调节免疫系统细胞的命运。通过清楚地识别这些细胞和分子的影响，这些研究将有助于了解干细胞如何在成人大脑中产生新的神经元。本项目通过培养大学生干细胞研究能力，向公众宣传非哺乳动物生物学研究的价值和神经系统终身可塑性的潜力，为社会做出贡献。本项目将转基因小龙虾产生的GFP阳性（GFP+）血细胞过继转移到非转基因受体动物体内，并确定它们的靶器官和分化特性。此外，从转基因小龙虾免疫系统的不同区域提取的GFP+细胞将用于过继转移，以确定能够产生成年神经元的细胞的组织来源。这些研究还将使用体外细胞迁移测定以及原位核酸杂交和免疫细胞化学来确定将血细胞吸引到神经原性小生境的局部指导线索，以定位已通过转录组分析确定的候选分子。最后，先天免疫系统和成人神经发生的5-HT激活的细胞因子（astakine 1; AST 1）途径的协调调节将进行测试。在改变5-HT水平后，将评估小生境、脑和免疫组织中AST 1的差异表达和定位。这些研究通过检验先天免疫系统细胞产生成人神经元的假设，挑战了胚胎神经组织的外胚层起源是成人大脑神经元唯一来源的经典观点。