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中，越来越多的证据表明全身感染或炎症可能加速疾病进展并加剧症状。全身性炎症和大脑之间的交流涉及大脑的巨噬细胞群，这些巨噬细胞群位于血管和大脑覆盖物的界面处，以及脑组织本身内的巨噬细胞，即小胶质细胞。在患病的大脑中，我们已经表明这些细胞的数量增加，对全身炎症更敏感：它们是“启动”的。在对全身炎症的反应中，它们产生能够干扰神经元之间的信号传导甚至杀死濒危神经元的炎症分子。拟议项目的计划成果包括了解调节免疫-大脑通信的基本机制和慢性神经退行性疾病的进展，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CSF 1 R的受体驱动的。此外，有证据支持通过该受体激活巨噬细胞也导致引发的想法。CSF 1 R的这两个关键生物学功能，增殖和启动的控制，将突出这一分子途径在慢性神经变性过程中的重要性。我们将使用一种新的技术将病毒载体递送到骨髓中，以标记血液来源的巨噬细胞，并确定它们是否有助于正常和患病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CSF 1 R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/或募集。我们将把我们在动物模型中的发现与对患有阿尔茨海默病的人的大脑的研究相关联，这些人死于或没有全身感染。最后，我们将研究CSF 1 R的药理学阻断是否可以防止巨噬细胞和小胶质细胞的启动和增殖，从而减轻全身炎症对患病大脑的有害影响。本文提出的研究目标是一种新的和雄心勃勃的方法来了解炎症在神经退行性疾病，并将产生重要的信息，神经免疫学和医学sciences.The了解小胶质细胞生物学在神经退行性疾病是至关重要的潜在的治疗方法，以控制有害的炎症反应的发展。这些潜在的干预措施可以改变或阻止神经退行性疾病，如阿尔茨海默病。拟议研究的潜在成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.