Project 3: Albayram

项目3--项目总结 新生儿脑损伤后二次免疫活性异常影响脑的临界期 发育，与神经发育障碍相关的长期行为异常。最多的 早产儿常见的脑损伤形式是生发基质出血(GMH)，可表现为 与非典型脑发育危险因素相关的病理生理改变。然而，人们对此知之甚少。 关于异常的次级免疫反应如何发生并持续在更高级别的大脑皮层和 GMH后发育中的大脑边缘区导致代偿性突触和神经元功能衰竭 导致行为异常的机制。最近的研究已经揭示了一个核心作用 补体作为促进脑损伤后继发性损伤的局部免疫识别机制 受伤。我们的初步数据表明，补体在传播致病后遗症方面也发挥了类似的作用。 GMH。使用GMH的小鼠模型，我们将研究补体依赖的神经炎症是如何在 新生儿脑损伤后导致初级代偿性突触和神经元机制失效 大脑的认知中心。我们将确定补体激活如何影响长期行为 与神经发育障碍相关的变化，我们将研究补体抑制作为一种潜在的 减轻GMH致病后遗症的治疗途径。此外，我们还将调查 继发性脑损伤传播过程中的异常神经元/突触消除，并专门研究 补体调理素-补体受体相互作用在这一过程中的作用。国家发展委员会将为我提供 通过获得CNDD核心和财政资源来支持研究，从而为项目提供关键支持 努力，以及职业发展和指导活动将确保未来成功获得NIH R01 在3年内，并过渡到一名在非兴奋剂领域的既定调查员。

PROJECT 3 – PROJECT SUMMARY Aberrant secondary immune activity after brain injury during neonatal life affects critical phases of brain development, with long-lasting behavioral abnormalities relevant to neurodevelopmental disorders. The most common form of brain injury in the preterm neonate is germinal matrix hemorrhage (GMH), which may display pathophysiological alterations relating to risk factors for atypical brain development. However, very little is known about how an aberrant secondary immune response that occurs and persists in the higher-order cortical and limbic regions of the developing brain following GMH leads to failure of compensatory synaptic and neuronal mechanisms and contributes to behavioral abnormalities. Recent studies have revealed a central role for complement in serving as a local immune recognition mechanism that promotes secondary injury after brain injury. Our preliminary data indicate a similar role for complement in propagating the pathogenic sequelae of GMH. Using a mouse model of GMH, we will investigate how complement dependent neuroinflammation in the neonatal brain following injury leads to failure of compensatory synaptic and neuronal mechanisms in primary cognitive centers of the brain. We will determine how complement activation impacts long-term behavioral changes relevant to neurodevelopment disorders, and we will investigate complement inhibition as a potential therapeutic approach to mitigate the pathogenic sequelae of GMH. Additionally, we will investigate the role of aberrant neuron/synapse elimination in the propagation of secondary brain injury, and specifically investigate a role for complement opsonin-complement receptor interactions in this process. The CNDD will provide me with critical support for the project through access to CNDD Cores and financial resources to support the research efforts, and the career development and mentoring activities will ensure future success in obtaining an NIH R01 within a 3-year period and a transition to an established investigator in the field of NDDs.