Transcription factors mediate postnatal neurogenesis from enteric glial cells

转录因子介导肠神经胶质细胞的产后神经发生

• 批准号: 9908442
• 负责人: Richard A Guyer
• 金额: $ 6.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908442
• 关键词: Adopted; Adult; Affect; Biology; Birth; Chemicals; Colitis; Crohn' s disease; Data; Development; Disease; Embryo; Embryonic Development; Enteral; Enteric Nervous System; Equilibrium; Esthesia; Fellowship; Functional disorder; Funding; Gastrointestinal tract structure; General Population; Genes; Genetic Transcription; Goals; Health; Homeostasis; Immune system; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; International; Intestines; Knockout Mice; Knowledge; Laboratories; Lead; Leadership; Learning; Maintenance; Mediating; Mentors; Modeling; Molecular; Mus; NBPhox protein; Natural regeneration; Neural Crest; Neural Crest Cell; Neuraxis; Neuroglia; Neurons; Neuropathy; Oral; Paper; Pathway interactions; Peripheral Nervous System; Phenotype; Play; Population; Process; Production; Research; Research Personnel; Role; Scientist; Signal Transduction; Small Interfering RNA; Source; Statistical Methods; Subgroup; System; Techniques; Technology; Testing; Therapeutic; Tissues; Training; Training Programs; Transgenes; Ulcerative Colitis; United States National Institutes of Health; Work; Writing; absorption; adult neurogenesis; career; cell motility; conditional knockout; density; experience; experimental study; gastrointestinal; gastrointestinal function; in vivo; inflammatory disease of the intestine; insight; knock-down; meetings; mouse model; nerve stem cell; nervous system disorder; neurogenesis; new therapeutic target; next generation; overexpression; postnatal; prenatal; programs; response; response to injury; single-cell RNA sequencing; skills; targeted treatment; therapeutic target; trait; transcription factor; transcriptome sequencing

PROJECT SUMMARY The enteric nervous system (ENS) plays a vital role in gastrointestinal biology by regulating gut motility, secretion, and absorption, and by interacting with the immune system. Dysregulation of the ENS thus contributes to many diseases, including the inflammatory bowel diseases (IBDs) ulcerative colitis (UC) and Crohn’s disease (CD). IBDs are associated with increased density of enteric neurons and activation of enteric glial cells, and existing evidence suggests that these effects directly contribute to the pathobiology of IBDs. Understanding the role of ENS components in UC and CD is thus critical for developing targeted therapies. Recent papers both from our group and from other laboratories have demonstrated that some ENS glial cells switch fates to become neurons in response to inflammation. The ENS glia thus contain a subset of neuronal progenitor cells, and inflammatory signals trigger this population to generate new neurons. However, it is not clear how glial cells alter their transcriptional program to generate neurons, and what subgroups of glia are involved in this process is unknown. The goal of this project is to test the hypothesis that specific transcription factors with known roles in prenatal neurogenesis induce postnatal neurogenesis in the ENS in response to inflammation. Phox2b is a transcription factor with critical roles in both ENS and central nervous system neurogenesis, and preliminary data shows that it induces cultured glia to adopt a neuronal phenotype. I hypothesize that colonic inflammation will trigger Phox2b-mediated neuronal fate acquisition in a subset of enteric glial cells. To test this hypothesis, I will use single cell RNA sequencing and a conditional Phox2b knockout mouse model. Completion of this project will significantly enhance our understanding of enteric glia in the pathophysiology of IBDs, and will reveal molecular pathways that may represent therapeutic targets. This work will also reveal glial subpopulations with potential to be harnessed therapeutically to regenerate missing neurons. In addition to the proposed research, this fellowship will provide training to plan, execute, and analyze data from experiments utilizing RNA sequencing techniques, to breed mice to generate tissue-specific conditional knockout models, to culture and manipulate primary enteric glial cells, to effectively communicate scientific data in writing and orally, and to manage and lead a scientific project. Upon completion of the fellowship, I will be prepared to launch my own career as an independent, NIH-funded scientist studying gastrointestinal biology.

项目概要 肠神经系统（ENS）通过调节肠道蠕动在胃肠生物学中发挥着至关重要的作用， 分泌、吸收以及与免疫系统相互作用。因此 ENS 失调 导致许多疾病，包括炎症性肠病（IBD）、溃疡性结肠炎（UC）和 克罗恩病（CD）。 IBD 与肠道神经元密度增加和肠道激活有关 神经胶质细胞和现有证据表明这些影响直接影响 IBD 的病理学。 因此，了解 ENS 成分在 UC 和 CD 中的作用对于开发靶向治疗至关重要。 我们小组和其他实验室最近发表的论文表明，一些 ENS 胶质细胞 改变命运成为对炎症做出反应的神经元。因此，ENS 神经胶质细胞包含神经元的一个子集 祖细胞和炎症信号触发该群体产生新的神经元。然而，它并不是 清楚神经胶质细胞如何改变其转录程序以产生神经元，以及神经胶质细胞有哪些亚群 参与这一过程的未知。该项目的目标是检验特定转录的假设 在产前神经发生中具有已知作用的因素会诱导 ENS 中的产后神经发生，以响应 炎。 Phox2b 是一种转录因子，在 ENS 和中枢神经系统中发挥着关键作用 神经发生，初步数据表明它诱导培养的神经胶质细胞采用神经元表型。我 假设结肠炎症将触发 Phox2b 介导的神经元命运获得 肠神经胶质细胞。为了验证这个假设，我将使用单细胞 RNA 测序和条件 Phox2b 基因敲除小鼠模型。该项目的完成将显着增强我们对肠胶质细胞的理解 IBD 的病理生理学，并将揭示可能代表治疗靶点的分子途径。这 这项工作还将揭示神经胶质亚群有可能被用于治疗性再生缺失 神经元。除了拟议的研究之外，该奖学金还将提供计划、执行和分析方面的培训 利用 RNA 测序技术培育小鼠以产生组织特异性的实验数据 条件敲除模型，培养和操作原代肠神经胶质细胞，有效沟通 书面和口头的科学数据，以及管理和领导科学项目。完成后 奖学金，我将准备开始自己的职业生涯，作为一名独立的、由 NIH 资助的科学家进行研究 胃肠生物学。