Imaging macrophage and microglial functional diversity in stroke

中风中巨噬细胞和小胶质细胞功能多样性的成像

• 批准号: 10285163
• 负责人: JOHN W CHEN
• 金额: $ 40.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285163
• 关键词: 3-Dimensional; Administrative Supplement; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid beta-Protein; Animals; Award; Axon; Blood - brain barrier anatomy; Cell Culture Techniques; Cells; Demyelinations; Development; Disease; Early Diagnosis; Enzymes; Event; Future; Goals; Grant; Human; Image; Immune; Inflammation; Knowledge; Mass Spectrum Analysis; Mediating; Microglia; Modeling; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Oxidative Stress; Parents; Pathogenesis; Pathology; Patient-Focused Outcomes; Patients; Phenotype; Play; Progressive Disease; Proteins; Proteomics; Reporting; Role; Stroke; Testing; Time; Translating; beta amyloid pathology; design; imaging agent; improved; in vitro Assay; in vivo; insight; macrophage; mouse model; neuroinflammation; novel therapeutics; parent project; prevent; prototype; response; targeted imaging; tau aggregation

Alzheimer's disease (AD) is a devastating and progressive disease without a cure. Long thought to be a consequence of AD, neuroinflammation is now recognized to be a key early event in the development of AD. Neuroinflammation in AD is predominately driven by innate immunity mediated by microglia. Aberrant neuroinflammatory response activates immune cells and releases enzymes and factor to generate oxidative stress that can directly damage neurons and axons, cause demyelination, and break down the blood-brain barrier (BBB), and has been found in patients with early stage AD. Current knowledge on these cells and their functions has been derived from indirect observations utilizing in vitro assays that prevent longitudinal tracking in living animals and patients. While imaging could potentially track inflammation in vivo, no imaging agent currently available can specifically report on microglia and characterize its functional phenotype in vivo. Thus, there is an unmet need to develop imaging agents that can specifically target different types of microglia, especially damaging-type microglia that participate in the AD pathogenesis. The novelty of this proposal is in 1) we have identified multiple potential markers that are unique to damaging microglia from the parent award, 2) at least four of these markers have been found to be associated with AD, and 3) we have developed prototype imaging agents for two of these targets that will now be tested and validated for AD. We hypothesize that the targets identified in stroke from the parent award can also be used to identify damaging microglia in AD. The goal of this administrative supplement proposal is to validate the stroke-derived imaging targets and potentially identify new imaging targets for damaging microglia in AD. The aims are 1A) identify and validate potential imaging targets for damaging microglia in AD, and 1B) validate potential imaging agents for damaging microglia in AD. Using high-throughput mass spectrometry proteomics, we will profile proteins from microglia subtypes and compare to macrophage subpopulations to verify existing targets found from the parent project and identify new unique targets for damaging microglia in AD. We will use two different mouse models of AD: 1) 5xFAD (β-amyloid pathology) and 2) rTg4510 (tau/neurofibrillary tangles pathology). We will also test using human cells obtained from a human 3D AD cell culture model that captures key features of human AD (β- amyloid, neurofibrillary tangles, neuroinflammation, and neurodegeneration). This supplement crossing stroke and AD will also provide a unique opportunity to observe how microglia are altered between these different diseases. We expect this supplement will enable future grants to develop and validate in vivo specific imaging agents to target damaging microglia in AD, and enable future studies to better understand the roles these microglia play in the development of AD and potentially other neurodegenerative diseases. Once translated, such an agent could enable early detection and timely treatment to improve AD patient outcome. The insight gained here may also spur development of novel therapies against damaging microglia.

阿尔茨海默病(AD)是一种毁灭性的进行性疾病，无法治愈。长期以来一直被认为是一种 阿尔茨海默病的后果，神经炎症现在被认为是阿尔茨海默病发生发展的关键早期事件。 阿尔茨海默病的神经炎症主要由小胶质细胞介导的先天免疫所驱动。反常的 神经炎性反应激活免疫细胞，释放酶和因子产生氧化 可直接损伤神经元和轴突，导致脱髓鞘，并破坏血脑的压力 屏障(BBB)，已在早期AD患者中发现。关于这些细胞和它们的最新知识 函数是从使用防止纵向跟踪的体外检测的间接观察中获得的 在活的动物和病人身上。虽然成像可以潜在地跟踪体内的炎症，但没有成像剂 目前可以在体内对小胶质细胞进行特异性报道，并对其功能表型进行表征。因此， 开发能够专门针对不同类型的小胶质细胞的显像剂的需求尚未得到满足， 尤其是参与AD发病机制的损伤性小胶质细胞。这项建议的新奇之处在于1) 我们已经从父母奖中确定了多个独特的损伤小胶质细胞的潜在标记，2) 这些标记中至少有四个已经被发现与AD有关，3)我们已经开发了原型 用于其中两个目标的显像剂，现在将对AD进行测试和验证。我们假设 在卒中中从父母奖中识别的靶点也可以用于识别AD中的破坏性小胶质细胞。这个 这项行政补充提案的目标是验证卒中衍生的成像目标，并潜在地 识别AD损伤小胶质细胞的新的成像靶点。目标是1)识别和验证潜力 AD中损伤小胶质细胞的成像靶点，以及1B)验证潜在的成像试剂的损伤 阿尔茨海默病的小胶质细胞。利用高通量质谱学蛋白质组学，我们将从小胶质细胞中提取蛋白质 分型并与巨噬细胞亚群进行比较，以验证从父项目中发现的现有目标 并确定损伤AD小胶质细胞的新的独特靶点。我们将使用两种不同的AD小鼠模型： 1)5xFAD(β-淀粉样变性)和2)rTg4510(tau/神经原纤维缠结病理)。我们还将测试使用 从人类3D AD细胞培养模型中获得的人类细胞，该模型捕捉了人类AD的关键特征(β- 淀粉样蛋白、神经原纤维缠结、神经炎症和神经变性)。这是交叉划线的补充 AD也将提供一个独特的机会来观察小胶质细胞是如何在不同的 疾病。我们希望这一补充将使未来的赠款能够开发和验证体内特定的成像 药物靶向阿尔茨海默病中受损的小胶质细胞，并使未来的研究更好地了解这些作用 小胶质细胞在阿尔茨海默病和潜在的其他神经退行性疾病的发展中发挥作用。一旦被翻译， 这样的制剂可以使早期发现和及时治疗，以改善AD患者的预后。洞察力 这一成果还可能刺激针对损伤小胶质细胞的新疗法的开发。