Regulation of microglial proliferation and its contribution to chronic neurodegeneration

众所周知，全身性炎症或感染与大脑沟通，并导致与疾病相关的症状。在患有阿尔茨海默病等大脑退行性疾病的人群中，越来越多的证据表明，全身性感染或炎症可能加速疾病进展并加剧症状。系统性炎症和大脑之间的交流涉及到大脑中的巨噬细胞群，它们位于血管和大脑覆盖物的界面，以及脑组织中的巨噬细胞，即小胶质细胞。在患病的大脑中，我们已经证明这些细胞数量增加，对全身性炎症更敏感：它们是“准备好的”。作为对全身性炎症的反应，它们产生炎症分子，这些炎症分子有能力干扰神经元之间的信号传导，甚至杀死濒临灭绝的神经元。拟议项目的计划成果包括了解调节免疫-脑通信和慢性神经退行性疾病进展的基本机制，从而有可能开发针对这些疾病的保护或治疗方法。在这个项目中，我们将确定患有神经退行性疾病的大脑中巨噬细胞和小胶质细胞数量增加的来源：它们是来自血液还是来自局部增殖。在慢性神经退行性变的动物模型中，我们有初步的数据表明，慢性神经退行性变期间的增殖是通过小胶质细胞上称为CSF1R的受体驱动的。此外，有证据支持巨噬细胞通过这种受体激活也会导致启动的观点。CSF1R的两个关键生物学功能，即控制增殖和启动，将突出该分子途径在慢性神经退行性疾病中的重要性。我们将使用一种新的技术，将病毒载体传递到骨髓，以标记血源性巨噬细胞，并确定它们是否有助于正常和病变大脑中的巨噬细胞和小胶质细胞。我们将研究全身性炎症是否也通过影响CSF1R的激活来驱动健康和患病大脑中巨噬细胞/小胶质细胞的增殖和募集。我们将把我们在动物模型中的发现与阿尔茨海默病患者的大脑研究联系起来，这些患者死于或不死于系统性感染。我们将最终研究CSF1R的药物阻断是否可以阻止巨噬细胞和小胶质细胞的启动和增殖，从而改善全身炎症对病变大脑的有害影响。这里提出的研究目标是一种新的和雄心勃勃的方法来理解神经退行性疾病中的炎症，并将为神经免疫学和医学科学界提供重要的信息。了解神经退行性疾病中的小胶质细胞生物学对于开发潜在的治疗方法来控制有害的炎症反应至关重要。这些潜在的干预措施可以改变或阻止像阿尔茨海默病这样的神经退行性疾病。拟议研究的潜在结果将迅速转化为神经病理学的临床，并将改善这种疾病患者的生活质量。

It is well known that systemic inflammation or infection communicates with the brain and leads to the symptoms associated with illness. In people with degenerative diseases of the brain such as Alzheimer's disease there is a growing body of evidence to show that systemic infections or inflammation may accelerate disease progression and exacerbate symptoms. Communication between systemic inflammation and the brain involves the macrophage populations of the brain, those that lie at the interface of the blood vessels and coverings of the brain and the macrophages within the brain tissue itself, the microglia. In a diseased brain we have shown that these cells increase in number and are more sensitive to the systemic inflammation: they are "primed". In response to systemic inflammation they generate inflammatory molecules that have the capacity to interfere with signalling between neurons and even kill endangered neurons. The planned outcomes of the proposed project include the understanding of fundamental mechanisms that regulate immune-to-brain communication and the progression of chronic neurodegeneration, leading to the potential for development of protective or therapeutic approaches against these diseases. In this project we will determine where the increased number of macrophages and microglia in brains with neurodegenerative disease come from: are they derived from the blood or from local proliferation. In animal models of chronic neurodegeneration we have preliminary data to show that proliferation during chronic neurodegeneration is driven through a receptor on the microglia called CSF1R. Also, there is evidence supporting the idea that activation of macrophages through this receptor also leads to priming. These two key biological functions of CSF1R, the control of proliferation and priming, would highlight the importance of this molecular pathway during chronic neurodegeneration. We will use a novel technique to deliver viral vectors to the bone marrow to label blood derived macrophages and determine whether they contribute to the macrophages and microglia in the normal and diseased brain. We will investigate whether systemic inflammation also drives proliferation and or recruitment of macrophages/microglia in healthy and diseased brains by influencing the activation of CSF1R. We will correlate our findings in animal models with studies of human brains from individuals with Alzheimer's disease who died with or without a systemic infection. We will finally investigate whether pharmacological blockade of the CSF1R can prevent both priming and proliferation of the macrophages and microglia and thus ameliorate the harmful effects of systemic inflammation on the diseased brain. The research objectives proposed here are a novel and ambitious approach to understanding inflammation in neurodegenerative diseases, and would generate important information for the neuroimmunological and medical sciences community.The understanding of microglial biology during neurodegenerative disease is crucial for the development of potential therapeutic approaches to control the harmful inflammatory reaction. These potential interventions could modify or arrest neurodegenerative diseases like Alzheimer disease. The potential outcomes of the proposed research would be rapidly translated into the clinics of neuropathology, and would improve the quality of life of patients with this disease.