mGluR5 inhibits microglial activation and neuronal cell death after TBI

 描述（由申请人提供）：创伤性脑损伤（TBI）触发延迟的生化变化，包括慢性神经炎症，导致组织损失和神经功能缺损。与临床TBI类似，我们已经证明M1（神经毒性）小胶质细胞在实验性TBI后数月至数年内长期活跃，导致进行性神经退行性变。我们的小组是第一个证明常规正构mGluR 5代谢型谷氨酸受体5（mGluR 5）激动剂能够减弱miR-155（一种关键的M1诱导microRNA（miR）），负调节M1表型，限制慢性小胶质细胞活化并减少进行性神经元丢失的能力，即使在TBI后一个月集中给药。重要的是，mGluR 5阳性变构调节剂（PAM）不仅减弱M1，还促进TBI后M2（神经保护性）小胶质细胞表型。这是通过对神经炎症的关键microRNA调节剂的联合作用，下调miR-155和上调M2诱导的miR-124来实现的。目前迫切需要确定选择性靶向治疗以限制创伤后炎性神经变性。我们的中心假设是，选择性mGluR 5 PAM通过同时减弱TBI诱导的慢性M1反应和促进神经保护性M2反应，对神经炎症/神经变性具有比正构激动剂更好的上级治疗效果;靶向潜在机制并使miR-155/miR-124平衡有利于miR-124的分子干预具有神经保护性。这些假设得到了强有力的初步研究的支持，表明mGluR 5 PAM降低miR-155，增加miR-124，逆转M1/M2失衡，以及减轻TBI后的神经元损失和神经损伤。提出的具体目标是：1）定义特定的mGluR 5 PAM 2）确定用mGluR 5 PAM延迟全身治疗对TBI诱导的慢性神经炎症、进行性神经变性和相关神经损伤的神经保护作用;和3）确定靶向miR-155/-124的延迟分子干预对TBI诱导的慢性神经炎症、进行性神经变性和相关神经损伤的神经保护作用。这些目标应该支持以下预期结果：TBI后mGluR 5 PAM的神经保护作用部分反映了逆转创伤后miR-155/miR-124变化;即使延迟全身给药，mGluR 5 PAM也具有稳健的神经保护作用; TBI后miR-155（下调）和miR-124（上调）的组合分子调节具有累加的神经保护作用。我们希望通过展示TBI后进行性神经变性的病理生理机制，并为改变M1/M2平衡的晚期治疗干预提供实验支持，从而产生重要的积极影响。

 DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) triggers delayed biochemical changes, including chronic neuroinflammation, that contribute to tissue loss and neurological deficits. Similar to clinical TBI, we have shown that M1 (neurotoxic) microglia are chronically active for months-to-years following experimental TBI, contributing to progressive neurodegeneration. Our group was the first to demonstrate the ability of conventional orthosteric mGluR5 metabotropic glutamate receptor 5 (mGluR5) agonists to attenuate miR-155, a key M1-inducing microRNA (miR), negatively regulate the M1 phenotype, limit chronic microglial activation and reduce progressive neuronal loss, even when administered centrally at one month after TBI. Importantly, mGluR5 positive allosteric modulators (PAMs) not only attenuate M1 but also promote M2 (neuroprotective) microglia phenotypes after TBI. This is accomplished by combined action on key microRNA modulators of neuroinflammation, down-regulating miR-155 and up-regulating the M2-inducing miR-124. There is an urgent unmet need to identify selective targeted therapies to limit posttraumatic inflammatory neurodegeneration. Our central hypothesis is that selective mGluR5 PAMs have superior therapeutic effects than orthosteric agonists on neuroinflammation/neurodegeneration by concurrently attenuating both TBI-induced chronic M1 responses and promoting neuroprotective M2 responses; molecular interventions that target the underlying mechanisms and tip the miR-155/miR-124 balance in favor of miR-124 are neuroprotective. These hypotheses are supported by strong preliminary studies showing that mGluR5 PAMs lower miR-155, increase miR-124, reverse M1/M2 imbalance, as well as attenuate neuronal loss and neurological impairments following TBI. The proposed specific aims are: 1) Define the specific mGluR5 PAM (VU0360172) signaling intermediaries that are responsible for down-regulating M1 and up-regulating M2 microglia; 2) Determine the neuroprotective effects of delayed systemic treatment with mGluR5 PAMs on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments; and 3) Determine the neuroprotective effects of delayed molecular interventions targeting miR-155/-124 on TBI-induced chronic neuroinflammation, progressive neurodegeneration and associated neurological impairments. These aims should support the following expected outcomes: neuroprotective effects of mGluR5 PAMs after TBI reflect, in part, reversing posttraumatic miR-155/miR-124 changes; that mGluR5 PAMs have robust neuroprotective effects even with delayed systemic administration; and that combined molecular modulation of miR-155 (down-regulation) and miR-124 (up-regulation) after TBI have additive neuroprotective effects. We expect to have an important positive impact by demonstrating the pathophysiological mechanisms underlying progressive neurodegeneration after TBI, and providing experimental support for late therapeutic interventions that alter M1/M2 balance.