Peripheral Macrophage Signatures of Inflammation in Neurodegenerative Diseases

神经退行性疾病中炎症的外周巨噬细胞特征

• 批准号: 7499672
• 负责人: HOWARD J. FEDEROFF
• 金额: $ 26.86万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499672
• 关键词: Affect; Age; Alzheimer' s Disease; American; Americas; Animals; Autopsy; Biochemical Pathway; Biological; Biological Markers; Brain region; Cessation of life; Chronic; Clinical; Development; Diagnosis; Diagnostic; Disease; Disease model; Functional disorder; Future; Gene Expression; Healthcare Systems; Hematopoietic System; Human; Individual; Inflammation; Late Onset Alzheimer Disease; Life; Mediating; Messenger RNA; Modeling; Molecular; Mouse Strains; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Parkinson Disease; Pathogenesis; Pathology; Peripheral; Pharmacotherapy; Population; Positioning Attribute; Process; Proteins; Reporting; Sensitivity and Specificity; Signal Pathway; Staging; Synapses; Syndrome; System; Testing; Therapeutic; Time; Tissues; Transcript; Transgenic Animals; Transgenic Model; Transgenic Organisms; United States; Wild Type Mouse; cell injury; cohort; cost; design; disorder control; human disease; human subject; improved; insight; macrophage; monocyte; prospective; synuclein; transcriptomics; transgenic model of alzheimer disease

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.

描述（由申请人提供）：晚发性阿尔茨海默病 (AD) 和帕金森病 (PD) 是慢性神经退行性疾病，影响着近 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，目前的疗法和治疗仅是症状性的，并且这些疾病仍然在不断地进展。因此，我们需要充分了解这些疾病的发病机制并设计分子诊断和改进的药物疗法，这对我们的国家和我们的医疗保健系统至关重要。有趣的是，虽然这些疾病通常在晚年出现临床表现，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。这导致了对该疾病的一种新兴观点，即一生中一系列不同的机械触发因素汇聚到共享的生化途径上，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断言，特定的下游生化途径介导在 AD 或 PD 中观察到的突触损失、细胞损伤和死亡。此外，许多病理生理变化将在共享这些信号传导途径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。具体来说，我们提出外周单核细胞/巨噬细胞受到早期致病过程的影响，并且可能有助于疾病病理学，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。我们建议使用这些疾病的两种小鼠模型，即 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+/+)，这将使我们能够在每种“疾病”的时间进程。在具体目标 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细胞/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特有的转录组谱（例如 AD、PD 与对照），并且更适用于常见的神经退行性过程。在具体目标 2 中，我们将测试从人类 AD、PD 和对照受试者中分离的外周单核细胞/巨噬细胞中这些谱的特异性和敏感性。我们假设这些研究中确定的转录组特征对于我们理解 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，充分了解这种疾病的发病机制并设计分子诊断和改进药物疗法对于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、特异且敏感的早期 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。