ACSL4 on the interface of metabolism and mental health

项目总结 智力残疾(ID)是最常见的发育性残疾原因，影响1-3%的 人口。不幸的是，大多数ID病例仍然缺乏有效的预防和干预选择。 在导致ID的各种原因中，大脑的代谢功能障碍起着至关重要的作用， 特别强调脂质，它是神经生物学和大脑功能的基本基础。 鉴于脂质代谢和中枢神经系统的极端复杂性，脂类和哪种 然而，它们中的一些种类调节神经元功能，促进ID的发展，但仍然很少 明白了。在此背景下，编码长链酰辅酶A合成酶家族同工酶的基因Acsl4被 在X连锁ID或Alport综合征中发现突变，从而为理解这两种精神疾病提供了一个有价值的接口 健康和脂类代谢。由于缺乏有效的方法在神经元中干扰它，ACSL4的S精确地 大脑的功能仍未确定。ACSL4的异常调节是否有助于疾病的发生 ID的也是未知的。最近，根据多条证据和我们的初步观察，我们 假设海马神经元中的ACSL4对神经元的发育和认知是必不可少的。我们 进一步提出小鼠海马区缺乏ACSL4通过影响学习和记忆(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 这种调节功能通过改变脂肪代谢在大脑中发挥作用(AIM-3)。通过最近的一项努力 为了研究ACSL4在体内脂肪组织中的作用，我们建立了FLOLID-ACSL4条件性小鼠 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 本实验建立了神经元特异性ACSL4基因敲除小鼠模型，对上述假说进行了验证。 目前应用中提出的研究将发现一种新的神经生物学机制，通过这种机制，脂质 ACSL4协调的动态平衡调节大脑中的突触和神经功能，并维持智力 健康。在分子、细胞和系统层面上的一系列严格、全面的方法将是 受雇的。这项研究的实施可能会揭示与肿瘤相关的新的生物学和新的生物标志物 精神障碍的病因和治疗，因此在基础和翻译方面都有很大的价值 关于心理健康的研究。

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.