Peripheral Macrophage Signatures of Inflammation in Neurodegenerative Diseases

描述(申请人提供)：迟发性阿尔茨海默病(AD)和帕金森氏病(PD)是一种慢性神经退行性疾病，影响近600万美国人，估计每年给美国经济造成超过1000亿美元的损失。不幸的是，目前的治疗方法和治疗只是有症状的，这些疾病仍在无情地进展。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的药物治疗方法，这对我们的国家和我们的卫生保健系统至关重要。有趣的是，虽然这些疾病通常在晚年出现在临床上，但各种尸检证据表明，AD和PD的病理特征，以及由此推断的疾病本身，都发生在个体生命的早期。这导致了对这种疾病的一种新的看法，即一生中一系列不同的机械触发因素汇聚在共同的生化途径上，从而引发一种表型相似的临床综合征和神经病理状态。这一趋同的病理生理学假说认为，特定的下游生化通路介导了AD或PD患者的突触丢失、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，并受到许多相同的病理生理变化的影响，这些变化是AD和PD的特征。具体地说，我们提出外周血单核/巨噬细胞受到早期致病过程的影响，并可能参与疾病病理，这将反映在转录和蛋白质水平和功能的变化上。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的治疗方法提供有价值的见解。我们建议使用两种这些疾病的小鼠模型，AD的三重转基因模型(3xTg-AD)和人类野生型突触核蛋白转基因PD的模型(hSYN-WT+/+)，这将使我们能够收集每种疾病的时间过程中的组织。在特定的目标1中，我们将收集这些转基因小鼠品系和野生型对照小鼠的外周血单核/巨噬细胞，并在三个时间点使用基因芯片询问基因表达。我们将确定针对每种疾病模型的转录图谱(例如，AD、PD和对照)，这将更适用于常见的神经退行性变过程。在特定目标2中，我们将在从人类AD、PD和对照组分离的外周血单核/巨噬细胞中测试这些图谱的特异性和敏感性。我们假设，这些研究中确定的转录特征将对我们理解AD和PD的疾病诊断、发病机制和治疗非常重要。随着美国“婴儿潮一代”的老龄化，需要充分了解这种疾病的发病机制，设计分子诊断方法和改进的药物疗法，这对我们的国家和我们的医疗保健系统至关重要。因此，有必要开发易于获得、可靠、特异和敏感的早期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.