ACSL4 on the interface of metabolism and mental health

ACSL4 代谢与心理健康的界面

• 批准号: 9789685
• 负责人: Dong Kong
• 金额: $ 20.19万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789685
• 关键词: Acyl Coenzyme A; Adipocytes; Adipose tissue; Adrenal Glands; Affect; Arachidonic Acids; Basic Science; Behavioral; Biology; Brain; Brain region; Cells; Coenzyme A Ligases; Cognition; Complex; Dendritic Spines; Development; Developmental Disabilities; Diagnosis; Drosophila genus; Enzymes; Esters; Etiology; Family; Fatty Acids; Gene Deletion; Genes; Genetic; Health; Hereditary nephritis; Hippocampus (Brain); Homeostasis; Human; Image; Impairment; Intellectual functioning disability; Isoenzymes; Knockout Mice; Learning; Link; Lipids; Liquid Chromatography; LoxP-flanked allele; Mediating; Memory; Mental Health; Mental Retardation; Mental disorders; Metabolic dysfunction; Metabolism; Modeling; Molecular; Morphology; Mus; Mutate; Mutation; Neuraxis; Neurobiology; Neurologic; Neurons; Neurophysiology - biologic function; Orthologous Gene; Pathogenesis; Pathologic; Patients; Peripheral; Physiological; Play; Population; Positioning Attribute; Prevention; Preventive Intervention; Rattus; Research; Role; Scientist; Specificity; Synapses; Synaptic plasticity; System; Technology; Testing; Therapeutic; Tissue Extracts; Tissues; Translational Research; United States; Visual system structure; X Chromosome; X-linked intellectual disability; base; behavioral study; brain tissue; cognitive disability; cognitive function; developmental disease; genetic association; high throughput analysis; in vivo; interest; knock-down; lipid metabolism; long chain fatty acid; mouse model; neurobiological mechanism; neuron development; novel; novel marker; preference; relating to nervous system; synaptic function; synaptogenesis; tandem mass spectrometry; tool; virus genetics

PROJECT SUMMARY Intellectual disability (ID) is the most frequent cause of developmental disabilities and affects 1-3% of the population. Most cases of ID, unfortunately, are still lacking effective prevention and intervention options. Among the heterogeneous causes of ID, metabolic dysfunctions in the brain are playing an essential role, with a particular emphasis on lipids, which form a fundamental basis for both neurobiology and brain function. Given the extreme complexity of lipid metabolism and the central nervous system, how lipids and which species of them regulate neuronal functions and contribute to the development of ID, however, are still poorly understood. In this context, Acsl4, a gene encoding an isozyme of long chain acyl-CoA synthetase family, was found mutated in X-linked ID or Alport syndrome, thus providing a valuable interface to understand both mental health and lipid metabolism. Due to the lack of effective approaches to perturb it in neurons, ACSL4’s precise functions in the brain are still undetermined. Whether dysregulations of ACSL4 contribute to the development of ID is also unknown. Recently, based on multiple lines of evidence and our preliminary observation, we hypothesize that ACSL4 in hippocampal neurons is essential for neuron development and cognition. We further propose that lacking ACSL4 in the mouse hippocampus affects learning and memory (Aim-1) by dampening synapse formation and synaptic plasticity (Aim-2). Importantly, we postulate that ACSL4 achieves such regulatory functions in the brain by altering lipid metabolism (Aim-3). Through a recent effort to investigate the role of ACSL4 in adipose tissue in vivo, we have established a floxed-Acsl4 conditional mouse model, which allows tissue-specific deletion of the gene in a cre-dependent manner. We then plan to leverage this mouse line to establish a neuron-specific ACSL4 knockout mouse model to assess the above hypotheses. The proposed studies in the current application will discover a novel neurobiological mechanism by which lipid homeostasis orchestrated by ACSL4 regulates synaptic and neural functions in the brain and maintains mental health. A battery of rigorous, comprehensive approaches at molecular, cellular and system levels will be employed. Fulfillment of the research will likely reveal new biology and novel biomarkers relevant to the etiology and treatment of mental disorders and will therefore be of great values in both basic and translational research on mental health.

项目概要 智力障碍 (ID) 是发育障碍的最常见原因，影响 1-3% 的人 不幸的是，大多数智力障碍病例仍然缺乏有效的预防和干预方案。 在 ID 的多种原因中，大脑代谢功能障碍发挥着重要作用，其中 特别强调脂质，它构成了神经生物学和大脑功能的基础。 鉴于脂质代谢和中枢神经系统的极端复杂性，脂质如何以及哪些 然而，它们中的物种调节神经功能并促进智力障碍的发展仍然很差 在这种情况下，Acsl4是一种编码长链酰基辅酶A合成酶家族同工酶的基因。 在 X 连锁 ID 或 Alport 综合征中发现突变，从而为理解心理和精神疾病提供了一个有价值的界面 由于缺乏有效的方法来干扰神经元中的健康和脂质代谢，ACSL4 的精确性。 ACSL4 的失调是否会导致发育仍不清楚。 最近，根据多方面的证据和我们的初步观察，我们得出的结论是： 我们发现海马神经元中的 ACSL4 对于神经元发育和认知至关重要。 进一步提出小鼠海马体中缺乏 ACSL4 通过以下方式影响学习和记忆 (Aim-1) 抑制突触形成和突触可塑性 (Aim-2) 重要的是，我们假设 ACSL4 实现了这一点。 最近的一项努力是通过改变脂质代谢来实现大脑的这种调节功能（Aim-3）。 为了研究ACSL4在体内脂肪组织中的作用，我们建立了floxed-Acsl4条件小鼠 模型，该模型允许以依赖于 cre 的方式对基因进行组织特异性删除，然后我们计划利用该模型。 以此小鼠系建立神经元特异性ACSL4敲除小鼠模型来评估上述假设。 当前申请中提出的研究将发现一种新的神经生物学机制，通过该机制脂质 ACSL4 协调的稳态调节大脑中的突触和神经功能并维持精神状态 将在分子、细胞和系统层面采取一系列严格、全面的方法。 这项研究的完成可能会揭示与该研究相关的新生物学和新生物标志物。 精神障碍的病因和治疗，因此在基础和转化方面都具有重要价值 心理健康研究。