MHC I Inhibition of Neuronal Repair Responses

描述（由申请人提供）： 在免疫系统中，MHCI以其抑制NK细胞和T细胞功能的能力而闻名，为预防自身反应性提供了关键机制。MHCI在CNS中的表达通常较低。然而，在红藻氨酸盐诱导的癫痫发作和CNS损伤后，MHCI表达在神经元上被局部诱导，并且许多研究已经观察到患有脑损伤、中风、癫痫和神经退行性疾病的患者的CNS中MHCI表达增加。最近，神经元MHCI被证明参与消除CNS中不适当的突触连接。此外，我们的初步结果表明，MHCI可以抑制神经元的生长在体外。基于这些观察结果，我们推测，诱导表达的MHCI神经元损伤后可能会抵消体内神经元的修复反应。为了验证这一假设，我们利用了一个充分表征的模型，发生后，单方面病变的穿通路径，结合转基因小鼠的基因工程表达低水平的MHCI对中枢神经系统神经元的代偿性神经元发芽。我们的初步结果表明，虽然这些转基因小鼠没有明显的发育中枢神经系统异常，他们严重减少了补偿发芽反应后中枢神经系统损伤。这一提议将进一步验证神经元MHCI可以抑制代偿性神经元发芽反应的假设。这将提供一个基础，从MHCI在神经发育和神经元修复的作用，可以进一步评估。这一建议开辟了一个新的研究领域，其结果可能提供重要的概念进展。可以想象，限制MHCI的神经抑制作用的治疗可能会导致新的临床方法来减轻神经病理学疾病。

DESCRIPTION (provided by applicant): In the immune system, MHCI is well known for its ability to suppress NK cell and T cell function, providing a key mechanism for preventing autoreactivity. MHCI expression in the CNS is generally low. However, MHCI expression is locally induced on neurons following kainate-induced seizures and CNS injury, and numerous studies have observed increases in MHCI expression in the CNS of patients with brain injury, stroke, epilepsy and neurodegenerative diseases. Recently, neuronal MHCI was shown to be involved in the elimination of inappropriate synaptic connections in the CNS. Moreover, our preliminary results indicate that MHCI can inhibit neuronal outgrowth in vitro. Based on these observations, we hypothesized that the induced expression of MHCI on neurons following injury might counteract neuronal repair responses in vivo. To test this hypothesis, we utilized a well-characterized model of compensatory neuronal sprouting that occurs following unilateral lesioning of the perforant path, combined with transgenic mice which were genetically engineered to express low levels of MHCI on CNS neurons. Our preliminary results indicate that although these transgenic mice had no apparent developmental CNS abnormalities, they have severely reduced compensatory sprouting responses following CNS injury. This proposal will further test the hypothesis that neuronal MHCI can inhibit compensatory neuronal sprouting responses. This will provide a foundation from which the role of MHCI in neurodevelopment and neuronal repair can be further assessed. This proposal opens a new area of research, the results of which may provide important conceptual advances. Conceivably, treatments that limit the neuroinhibitory effects of MHCI could lead to new clinical approaches to mitigate neuropathological disorders.