Microglia modulate ethanol impact on CNS development.

描述(由申请人提供)：尽管胎儿酒精谱系障碍(FASD)是已知的导致智力低下的主要原因，并会导致认知和行为异常，但神经发病的潜在机制尚不清楚。我们已经确定小胶质细胞是酒精在发育中的中枢神经系统中致病的靶点，并与FASD相关。使用我们的FASD新生啮齿动物模型，我们发现乙醇会导致小胶质细胞死亡。存活的小胶质细胞表达一种激活的表型，表现为明显的形态变化和抗原激活标志物的表达。我们发现了乙醇失控的信号通路，并发现乙醇抑制了PPAR3的表达，PPAR3具有抗炎和神经保护作用。尤其耐人寻味的是，PPAR3激动剂治疗可以预防小脑畸形、生长迟缓、小胶质细胞和神经元死亡以及炎症病理。我们假设乙醇抑制PPAR3信号有助于细胞死亡，进一步，PPAR3激动剂通过PPAR3受体依赖的机制保护乙醇。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同培养进行研究。(1)我们将确定PPAR3激动剂对乙醇的保护机制。这些研究将确定PPAR3激动剂是否通过受体依赖或受体非依赖机制调节小胶质细胞和神经元的存活。维甲酸X受体-1(RXR1)的作用也将被评估。(2)FDA批准的几种PPAR3和RXR1激动剂预防乙醇诱导的神经元和小胶质细胞死亡和/或预防神经炎性病变的能力将被确定，并建立相对疗效。将探讨激动剂引起靶向炎症分子变化的能力，以确定激动剂保护的机制，并为药理和治疗研究发现新的候选者。拟议的研究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的治疗干预提供新的机会。临床前FASD大鼠模型的创新应用，以确定预防乙醇神经病理的新疗法的机制和有效性，为FASD研究的未来提供了希望。。 与公共卫生相关：尽管胎儿酒精谱系障碍(FASD)是智力低下的主要已知原因，并会导致认知和行为异常。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促炎表型。我们确定了乙醇失控的信号通路，并发现乙醇抑制了抗炎和神经保护PPAR3通路。尤其耐人寻味的是，PPAR3激动剂可以阻断乙醇的神经发病。本研究将确定PPAR3激动剂对乙醇的保护机制。此外，FDA批准的PPAR3和RXR1激动剂防止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将被确定，并建立相对疗效。拟议的研究结果将是创新和重要的，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.