Microglia modulate ethanol impact on CNS development.

描述（由申请人提供）：虽然胎儿酒精谱系障碍（FASD）是智力迟钝的主要已知原因，并产生认知和行为异常，但神经发病机制的基本机制尚不清楚。我们已经确定了小胶质细胞作为发展中的CNS中乙醇发病机制的靶点，并与FASD相关。使用我们的FASD新生啮齿动物模型，我们发现乙醇导致小胶质细胞死亡。存活的小胶质细胞表达活化的表型，明显的形态学变化和抗原活化标志物的表达。我们确定了乙醇失调的信号通路，并发现乙醇抑制过氧化物酶体增殖物激活受体3（PPAR 3）的表达，其活性是抗炎和神经保护。特别有趣的是，PPAR 3激动剂治疗预防了微脑畸形、生长迟缓、小胶质细胞和神经元死亡以及炎性病理。我们推测，乙醇抑制PPAR 3信号转导有助于细胞死亡，而且，PPAR 3激动剂通过PPAR 3受体依赖性机制保护细胞免受乙醇的侵害。这将使用我们的FASD大鼠模型以及小胶质细胞和神经元的共培养物来研究。(1)我们将确定PPAR 3激动剂对乙醇的保护机制。这些研究将确定PPAR 3激动剂是否通过受体依赖性或受体非依赖性机制调节小胶质细胞和神经元存活。还将评价类维生素A X受体-1（RXR 1）的作用。(2)将确定几种FDA批准的PPAR 3和RXR 1激动剂预防乙醇诱导的神经元和小胶质细胞死亡和/或预防神经炎性病理的能力，并建立相对功效。激动剂引起靶向炎症分子变化的能力将被探测，以确定不仅激动剂保护的机制，但发现新的候选药物和治疗研究。这项研究的结果将具有重要意义，因为它们将带来对FASD机制的新理解，并为乙醇引起的细胞死亡和炎症病理学的治疗干预提供新的机会。FASD临床前大鼠模型的创新应用，以确定新的治疗方法，以防止乙醇神经病理学的机制和疗效，为FASD研究的未来带来了希望。. 公共卫生相关性：虽然胎儿酒精谱系障碍（FASD）是智力迟钝的主要已知原因，并产生认知和行为异常。我们已经发现乙醇导致小胶质细胞死亡，并且存活的小胶质细胞表达活化的促炎表型。我们确定了乙醇引起的信号通路失调，并发现乙醇抑制了抗炎和神经保护的PPAR 3通路。特别有趣的是，PPAR 3激动剂可以阻断乙醇神经发病机制。本研究将确定PPAR 3激动剂对乙醇的保护机制。此外，将确定FDA批准的PPAR 3和RXR 1激动剂预防乙醇诱导的神经元和小胶质细胞死亡和/或预防神经炎性病理的能力，并建立相对功效。拟议的调查结果将是创新和重要的，因为它们将带来FASD机制的新认识，并为乙醇引起的细胞死亡和炎症病理学的治疗干预提供新的机会。

DESCRIPTION (provided by applicant): Although fetal alcohol spectrum disorders (FASD) is the leading known cause of mental retardation and produces cognitive and behavioral abnormalities, the underlying mechanisms of neuropathogenesis are poorly defined. We have identified microglia as targets of ethanol pathogenesis in the developing CNS, with relevant translation to FASD. Using our neonatal rodent model of FASD, we discovered that ethanol causes microglial death. Surviving microglia express an activated phenotype, evident with morphological change and expression of antigenic activation markers. We identified signaling pathways that are dysregulated by ethanol and found that ethanol suppresses expression of peroxisome proliferator-activated receptor-3 (PPAR3), whose activity is anti-inflammatory and neuroprotective. Particularly intriguing, PPAR3 agonist treatment prevents microencephaly, growth retardation, microglial and neuronal death, and inflammatory pathology. We hypothesize that ethanol suppression of PPAR3 signaling contributes to cell death and, further, that PPAR3 agonists protect against ethanol through a PPAR3 receptor-dependent mechanism. This will be investigated using our rat model of FASD and co-cultures of microglia and neurons. (1) We will determine the mechanism of PPAR3 agonist protection against ethanol. These studies will determine if PPAR3 agonists modulate microglial and neuronal survival through receptor-dependent or receptor-independent mechanisms. The contribution of retinoid X receptor-1 (RXR1) will also be evaluated. (2) The ability of several FDA-approved PPAR3 and RXR1 agonists to prevent ethanol-induced death of neurons and microglia and/or prevent neuroinflammatory pathology will be determined and relative efficacy established. The ability of agonists to evoke change in targeted inflammatory molecules will be probed to identify not only the mechanism of agonist protection but uncover new candidates for pharmacological and therapeutic investigation. The results of the proposed investigation will be significant because they will bring new understanding of FASD mechanisms and provide new opportunities for therapeutic intervention in the cell death and inflammatory pathology caused by ethanol. Innovative application of the preclinical rat model of FASD to determine the mechanism and efficacy of novel treatments to prevent ethanol neuropathology holds promise for the future of FASD research. . PUBLIC HEALTH RELEVANCE: Although fetal alcohol spectrum disorders (FASD) is the leading known cause of mental retardation and produces cognitive and behavioral abnormalities. We have found that ethanol causes microglial death and that surviving microglia express an activated, pro-inflammatory phenotype. We identified signaling pathways that are dysregulated by ethanol and found that ethanol suppresses the anti-inflammatory and neuroprotective PPAR3 pathways. Particularly intriguing, PPAR3 agonists can block ethanol neuropathogenesis. This study will determine the mechanism of PPAR3 agonist protection against ethanol. In addition, the ability of FDA- approved PPAR3 and RXR1 agonists to prevent ethanol-induced death of neurons and microglia and/or prevent neuroinflammatory pathology will be determined and relative efficacy established. The results of the proposed investigation will be innovative and significant because they will bring new understanding of FASD mechanisms and provide new opportunities for therapeutic intervention in the cell death and inflammatory pathology caused by ethanol.