Peripheral Macrophage Signatures of Inflammation in Neurodegenerative Diseases

描述（由申请人提供）：晚发性阿尔茨海默病（AD）和帕金森病（PD）是影响近600万美国人的慢性神经退行性疾病，估计每年使美国经济损失超过1000亿美元。不幸的是，目前的疗法和治疗只是症状性的，这些疾病仍在不断发展。因此，我们需要充分了解这些疾病的发病机制，设计分子诊断和改进药物治疗对我们的国家和我们的卫生保健系统至关重要。有趣的是，虽然这些疾病在临床上通常在生命的后期表现出来，但各种尸检证据表明，AD和PD的病理特征，以及疾病本身，都发生在个体生命的早期。这导致了一种新的疾病观点，即一生中一系列不同的机制触发因素汇聚在共同的生化途径上，从而引发表型相似的临床综合征和神经病理状态。这种趋同的病理生理学假说认为，特定的下游生化途径介导了AD或PD中观察到的突触丧失、细胞损伤和死亡。此外，许多这些病理生理变化将在共享这些信号通路的外周系统中表现出来。我们假设造血系统与神经系统共享许多细胞信号通路，并受到许多与AD和PD相同的病理生理变化的影响。具体而言，我们认为外周单核/巨噬细胞受到早期致病过程的影响，并可能参与疾病病理，这将反映在转录物和蛋白质水平和功能的改变上。因此，这些变化将作为疾病诊断和进展的重要先行生物标志物，并应为疾病病理生理学和潜在治疗提供有价值的见解。我们建议使用这两种疾病的小鼠模型，AD的三重转基因模型（3xTg-AD）和PD的人类野生型突触核蛋白转基因模型（hSYN-WT+/+），这将使我们能够收集每一种“疾病”的时间过程中的组织。在Specific Aim 1中，我们将从这些转基因小鼠品系和野生型对照小鼠中收集外周单核/巨噬细胞，并在三个时间点使用微阵列询问基因表达。我们将确定每种疾病模型（例如AD、PD和对照）特异性的转录组谱，这将更广泛地应用于常见的神经退行性过程。在Specific Aim 2中，我们将在从人AD、PD和对照对象中分离的外周单核/巨噬细胞中测试这些谱的特异性和敏感性。我们假设在这些研究中发现的转录组特征将对我们理解AD和PD的疾病诊断、发病机制和治疗具有重要意义。随着美国“婴儿潮一代”的老龄化，充分了解这种疾病的发病机制、设计分子诊断和改进药物治疗对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发易于获取、稳健、特异、敏感的早期AD和PD生物标志物，这将极大地促进这些疾病的诊断和治疗。

DESCRIPTION (provided by applicant): Late onset Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative disorders that affect nearly six million Americans and are estimated to cost the United States economy over $100 billion annually. Unfortunately, current therapies and treatments are only symptomatic and these diseases remain relentlessly progressive. Thus, our need to fully understand the pathogenesis of these diseases and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and to our health care systems. Interestingly, while these diseases typically manifest clinically later in life, a variety of postmortem evidence suggests that the pathological hallmarks of both AD and PD, and by inference the disease itself, occur early in an individual's life. This has led to an emerging view of the disease whereby a set of disparate mechanistic triggers over a lifetime converge upon shared biochemical pathways to elicit a phenotypically similar clinical syndrome and neuropathological state. This convergent pathophysiological hypothesis asserts that specific downstream biochemical pathways mediate the synaptic loss, cellular injury, and death observed in either AD or PD. Furthermore, many of these pathophysiological changes will be manifest in peripheral systems, which share these signaling pathways. We hypothesize that the hematopoietic system shares many cellular signaling pathways with the nervous system and is affected by many of the same pathophysiological changes that characterize AD and PD. Specifically, we propose that peripheral monocytes/macrophages are affected by early pathogenic processes, as well as may contribute to disease pathology, which will be reflected in alterations in transcript and protein levels and functions. As such, these changes will serve as important antecedent biomarkers for disease diagnosis and progression and should provide valuable insights into disease pathophysiology and potential therapeutics. We propose to use two murine models of these diseases, the triple transgenic model of AD (3xTg-AD) and the human wild-type synuclein transgenic model of PD (hSYN-WT+/+), which will allow us to collect tissues over the time course of each "disease." In Specific Aim 1 we will collect peripheral monocytes/macrophages from these transgenic mouse strains and wild type control mice and interrogate gene expression using microarrays at three time points. We will identify transcriptomic profiles that will be specific for each disease model (e.g. AD vs. PD vs. control) and that will be more generalizable to common neurodegenerative processes. In Specific Aim 2 we will test the specificity and sensitivity of these profiles in peripheral monocytes/macrophages isolated from human AD, PD, and control subjects. We hypothesize that the transcriptomic signatures identified in these studies will be important to our understanding of disease diagnosis, pathogenesis, and therapy in AD and PD. With the aging of America's "baby boomers" the need to fully understand the pathogenesis of this disease and to design molecular diagnostics and improved pharmacotherapies is vitally important to our nation and our health care systems. As such, it is necessary to develop easily accessible, robust, specific, and sensitive biomarkers of early AD and PD, which would greatly facilitate the diagnosis and treatment of these diseases.