Regulation of Enteric Nervous System Function by Group 3 Innate Lymphoid Cells

第 3 组先天淋巴细胞对肠神经系统功能的调节

• 批准号: 10679303
• 负责人: Jordan Zheng Zhou
• 金额: $ 6.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679303
• 关键词: Address; Birth; Bone Morphogenetic Proteins; Brain; Cells; Central Nervous System; Collection; Colon Carcinoma; Communication; Complex; Data; Data Set; Development; Disease; Endowment; Enteral; Enteric Nervous System; Feedback; Gastrointestinal Diseases; Gastrointestinal Transit; Genes; Goals; Growth Factor; Health; Hematopoietic; Homeostasis; Human; Immune; Immune Tolerance; Immune system; Immunity; Inflammation; Inflammatory Bowel Diseases; Interleukins; Intestines; Irritable Bowel Syndrome; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Link; Literature; Lymphocyte; Lymphoid; Lymphoid Cell; Lymphoid Tissue; Macrophage; Malignant neoplasm of gastrointestinal tract; Mediating; Modeling; Molecular; Mucous Membrane; Mus; Myenteric Plexus; Nervous System Physiology; Neural Pathways; Neuroglia; Neuroimmune; Neuronal Differentiation; Neurons; Neuropeptides; Nutrient; Pathway interactions; Patients; Peripheral; Peripheral Nervous System; Peristalsis; Population; Production; Regulation; Research Personnel; Role; Sampling; Science; Signal Transduction; Stimulus; System; Therapeutic; Time; Tissues; Translating; Vasoactive Intestinal Peptide; absorption; cell motility; cytokine; density; enteric infection; gene product; gut inflammation; immunoregulation; in vivo; interleukin-22; microbiota; mouse model; nervous system development; neuron development; neurotrophic factor; novel; nutrient absorption; pathogenic microbe; proto-oncogene protein c-ret; receptor; response; single-cell RNA sequencing; training opportunity; transcription factor

PROJECT SUMMARY The enteric nervous system (ENS) is critical for controlling key intestinal functions such as peristalsis and nutrient absorption. Emerging paradigms indicate that interactions between neurons and immune cells fundamentally impact immunity and inflammation in peripheral tissues. Recently, it has been shown that the ENS can act on the intestinal immune system to modify the function of innate lymphoid cells (ILCs). However, despite these advances, the role of ILCs in ENS function remains unexplored. In my preliminary studies, I defined that ILCs are genetically poised to interact with the ENS and support their development or function. By examining a specific factor produce by ILCs, I defined how it is regulated and developed a lineage-specific knockout to demonstrate this pathway plays a role in augmenting the ENS. To goals of this proposal are, in Aim 1, to utilize in vivo and ex vivo models to determine the molecular mechanisms that regulate ILCs and associated factors, and, in Aim 2, to determine the cellular mechanisms by which ILC-derived factors impacts the ENS and the importance of this interaction in maintaining ENS homeostasis during inflammation. Collectively, these two aims will critically define a novel molecular mechanism by which ILCs impact ENS function in states of intestinal health and disease, which could provoke novel preventative, therapeutic or curative strategies. Further, it will create an outstanding training opportunity for my continued development in science and eventual transition to become an independent academic researcher.

项目摘要 肠神经系统（ENS）对于控制关键的肠道功能如消化和营养至关重要 吸收新兴的范例表明，神经元和免疫细胞之间的相互作用从根本上 影响外周组织的免疫力和炎症。最近，已经表明ENS可以作用于 肠道免疫系统，以修改先天淋巴细胞（ILC）的功能。然而，尽管这些 尽管研究进展缓慢，但ILC在ENS功能中的作用仍未被探索。在我的初步研究中，我定义了ILC 在基因上准备与ENS相互作用并支持其发育或功能。通过检查特定的 由于ILCs产生的因子，我定义了它是如何调节的，并开发了一种谱系特异性敲除来证明 该途径在增强ENS中起作用。在目的1中，该提议的目标是利用体内和体外的方法， 体内模型以确定调节ILC和相关因子的分子机制，并且，在目的2中， 确定ILC衍生因子影响ENS的细胞机制及其重要性 在炎症期间维持ENS稳态的相互作用。总的来说，这两个目标将批判性地定义 ILC在肠道健康和疾病状态下影响ENS功能的新分子机制， 这可能引发新的预防、治疗或治愈策略。此外，它将创造一个杰出的 培训机会，让我在科学方面继续发展，并最终过渡到成为一名独立的 学术研究者