Lymphatic dysfunction in neurodevelopmental disorders and associated behaviors

神经发育障碍和相关行为中的淋巴功能障碍

• 批准号: 10852068
• 负责人: Antoine Louveau
• 金额: $ 40.25万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852068
• 关键词: Address; Adult; Attention Deficit Disorder; Behavior; Behavioral; Brain; Calcium; Cell Maintenance; Cells; Cerebrospinal Fluid; Circulation; Complement; Cytoskeletal Proteins; Data; Development; Disease; Drainage procedure; Excision; FMR1; Fragile X Syndrome; Functional disorder; Gene Expression; Genes; Goals; Health; Homeostasis; Image; Immune; Interferon Type II; Knockout Mice; Knowledge; Lymphatic; Lymphatic Endothelial Cells; Lymphatic function; Lymphocyte; Maintenance; Menin; Meningeal; Meningeal lymphatic system; Meninges; Modeling; Molecular; Morphology; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Pathway interactions; Pattern; Population; Prefrontal Cortex; Production; Proliferating; Properdin; Proteins; Proteomics; Regulation; Role; Scheme; Signal Transduction; Social Behavior; Symptoms; System; T cell regulation; T-Lymphocyte; Testing; Therapeutic; Tight Junctions; Vascular Endothelial Growth Factor C; Viral; Width; adherent junction; aged; autism spectrum disorder; behavioral impairment; brain parenchyma; cognitive function; improved; lymphatic drainage; lymphatic dysfunction; molecular targeted therapies; mouse model; neuroinflammation; neuronal circuitry; new therapeutic target; novel therapeutics; postnatal; protein expression; social; social deficits; transcriptomic profiling; transcriptomics; wasting

PROJECT SUMMARY/ABSTRACT This project aims at understanding the molecular mechanisms governing lymphatic dysfunction in a mouse model of neurodevelopmental disorder, i.e. the fmr1-KO mice, and their involvement in social and behavior. Meningeal lymphatic drainage, an essential system for the maintenance of brain function in adult and aged mice, was recently demonstrated develop postnatally during a critical window of brain maturation. We found that fmr1, the gene responsible for Fragile X Syndrome, is expressed in lymphatic endothelial cells, and that loss of fmr1 results in altered meningeal lymphatic morphology and function, via regulation of junction protein patterning. Furthermore, we found that altered lymphatic function in fmr1-KO mice results in decrease IFNg production (essential for neuronal homeostasis)in the meninges, that is rescued upon drainage improvement Finally, restoring draining function results in improved neuronal activation and social behavior in fmr1-KO mice. We therefore hypothesize that meningeal lymphatic dysfunction, through dysregulation of local immune cells, contributes to behavioral impairments in Fragile X. Guided by our preliminary data, we propose to address our hypothesis using the following aims: Aim1: Determine how fmr1 regulates meningeal lymphatic function. Aim2: Decipher the role of fmr1-induced lymphatic dysfunction in IFN T cell maintenance. Aim3: Address the contribution of meningeal lymphatic dysfunction in FXS-associated social behavior Collectively, Our proposed studies will have a broad impact by: a) characterizing meningeal lymphatic function in FXS; b) deciphering new molecular regulators of lymphatic function; c) demonstrating the central role of the meningeal lymphatic in the regulation of social behavior d) identifying and characterizing new molecular targets for the treatment of FXS; and e) providing evidence that the meningeal lymphatics represent a novel target for therapeutic strategies in neurodevelopmental disorders.

项目摘要/摘要 该项目旨在了解淋巴功能障碍的分子机制。 神经发育障碍的小鼠模型，即fmr1-KO小鼠及其参与社会和 行为。脑膜淋巴引流是维持成人和成人脑功能的重要系统 老龄小鼠，最近被证明是在大脑成熟的关键窗口中出生后发育的。我们 发现导致脆性X综合征的基因fmr1在淋巴管内皮细胞中表达，以及 Fmr1的缺失通过调节连接导致脑膜淋巴形态和功能的改变。 蛋白质构图。此外，我们还发现，fmr1-ko小鼠淋巴功能的改变会导致淋巴功能下降。 脑膜中产生的干扰素(对神经元动态平衡是必不可少的)，在引流时被挽救 改善最后，恢复引流功能会改善神经元的激活和社会行为 FMR1-KO小鼠。因此，我们假设，脑膜淋巴功能障碍，通过局部调节失调 免疫细胞，对脆性X的行为损害有贡献。 在我们初步数据的指导下，我们建议通过以下目标来解决我们的假设： 目的：探讨fmr1对脑膜淋巴功能的调节作用。 目的：破译fmr1诱导的淋巴功能障碍在干扰素T细胞维持中的作用。 目的：探讨脑膜淋巴功能障碍在FXS相关社会行为中的作用 总而言之，我们拟议的研究将产生广泛的影响：a)表征脑膜淋巴 在FXS中的作用；b)破译淋巴功能的新分子调节器；c)展示中枢 脑膜淋巴管在调节社会行为中的作用d)识别和表征新的 治疗FXS的分子靶点；以及e)提供证据表明脑膜淋巴管代表 神经发育障碍治疗策略的新靶点。