Elucidating the role of NK cells in Lewy body diseases

阐明 NK 细胞在路易体疾病中的作用

• 批准号: 10328911
• 负责人: Jae Kyung Lee
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328911
• 关键词: Address; Age; Allogenic; Attenuated; B-Lymphocytes; Blood; Brain; Cancerous; Cell Count; Cell physiology; Cells; Cellular Immunity; Corpus striatum structure; Data; Disease Progression; Enteric Nervous System; Extracellular Fluid; FYN gene; Immune; Immune response; Immune system; Immunotherapeutic agent; In Vitro; Infiltration; Inflammation; Infusion procedures; Leukocytes; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy body pathology; Ligands; Lymphocyte; Mediating; Microglia; Monitor; Multiple System Atrophy; Mus; Natural Killer Cells; Nerve; Nerve Degeneration; Neurons; Outcome; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Phenotype; Physiological; Play; Reporting; Research; Role; Scheme; Severity of illness; Substantia nigra structure; Surface; T-Lymphocyte; Testing; Tissues; Travel; Virus; Work; age related neurodegeneration; alpha synuclein; antimicrobial; base; chemokine; extracellular; gamma-Chemokines; gastrointestinal system; gut homeostasis; in vivo; innovation; interest; member; migration; mouse model; nervous system disorder; neuroinflammation; neuropathology; neuroprotection; neurotoxicity; novel; peripheral blood; pre-clinical; receptor; receptor binding; receptor expression; repaired; senescence; synuclein; synucleinopathy

PROJECT SUMMARY/ABSTRACT Lewy body diseases including Parkinson's disease (PD), Lewy body dementia (LBD), and multiple system atrophy are characterized by the accumulation of aggregated alpha-synuclein (α-syn) protein, which is the principal component of Lewy bodies (LBs). Neuroinflammation is the hallmark of Lewy body diseases and the role of the immune system has been implicated in the progression of synuclein pathology and neuropathology. However, the role of cellular immunity in promoting neurodegeneration or exerting neuroprotection remains unclear. We established a preclinical mouse model of α-synucleinopathy and showed a robust increase in immune responses in the CNS and the periphery. We noted significantly increased peripheral leukocytes including natural killer (NK) cells in the mouse model of α-synucleinopathy. As innate immune cells, NK cells are of particular interest for neurological disorders because they are modified in the periphery and/or travel into the CNS. It has been shown that NK cell numbers are increased in the blood of PD patients compared to age- matched controls and their activity is associated with disease severity. However, the role of NK cells in the context of PD has never been explored. We recently reported NK cells are present in the substantia nigra of post mortem brains of PD and LBD patients. Based on our experimental data, NK cells efficiently clear α-syn aggregates and in vivo depletion of NK cells results in exacerbated synuclein pathology, neuroinflammation, and striatal degeneration in a preclinical mouse model of α-syn aggregation. The proposed study will investigate the mechanism (s) by which NK cells reduces α-syn burden, modulate inflammation, and exert neuroprotection in the CNS and periphery. We will use both in vitro and in vivo mouse model of synucleinopathies to address the physiological role of NK cells in the context of Lewy body diseases. To test our central hypothesis and achieve our objective we propose three specific aims as follows: In Aim 1, we will investigate the mechanism by which NK cells scavenge α-syn and modulate α-syn-induced inflammation and neurotoxicity. In Aim 2, we will determine whether NK cells are neuroprotective in a mouse model of α-syn aggregations. In Aim 3, we will determine if peripheral NK cell infiltration into the CNS is essential for neuroprotection. To date, there are no therapies available to slow or stop disease progression of synucleinopathies. Our study will provide a comprehensive understanding of the role of NK cells in the context of Lewy body diseases. Therefore, this work can have a positive impact by providing a scientific basis for pursuing NK cells as a potential immunotherapeutic target for aged-related neurodegenerative diseases.

项目总结/摘要 路易体疾病包括帕金森病（PD）、路易体痴呆（LBD）和多系统 萎缩的特征是聚集的α-突触核蛋白（α-syn）蛋白的积累，这是 路易体（Lewy bodies，LBs）神经炎症是路易体病的标志， 免疫系统的作用与突触核蛋白病理学和神经病理学的进展有关。 然而，细胞免疫在促进神经退行性变或发挥神经保护作用方面的作用仍然存在 不清楚我们建立了一个α-突触核蛋白病的临床前小鼠模型，并显示出α-突触核蛋白病的显著增加。 中枢神经系统和外周的免疫反应。我们注意到外周血白细胞显著增加 包括在α-突触核蛋白病小鼠模型中的自然杀伤（NK）细胞。作为先天免疫细胞，NK细胞 因为它们在外周被修饰和/或进入 CNS。已经表明，与年龄相比，PD患者血液中的NK细胞数量增加。 匹配的对照，并且它们的活性与疾病的严重程度相关。然而，NK细胞在肿瘤发生中的作用尚不清楚。 PD的背景从未被探索过。我们最近报道了NK细胞存在于黑质中， PD和LBD患者的死后大脑。根据我们的实验数据，NK细胞有效地清除α-syn， NK细胞的聚集和体内耗竭导致突触核蛋白病理学，神经炎症， 和纹状体变性。拟定的研究将 研究NK细胞减少α-syn负荷、调节炎症并发挥作用的机制。 在中枢神经系统和外周神经保护。我们将使用体外和体内小鼠模型， 突触核蛋白病，以解决NK细胞在路易体病的背景下的生理作用。测试 我们的中心假设和实现我们的目标，我们提出了三个具体目标如下：在目标1，我们将 研究NK细胞抑制α-syn和调节α-syn诱导的炎症的机制， 神经毒性在目标2中，我们将确定NK细胞是否在α-syn小鼠模型中具有神经保护作用， 聚合。在目标3中，我们将确定外周NK细胞浸润到CNS中是否是维持中枢神经系统功能所必需的。 神经保护到目前为止，还没有可用的治疗方法来减缓或阻止疾病进展。 共核蛋白病我们的研究将提供一个全面的了解NK细胞的作用，在这种情况下， 路易体病因此，这项工作可以通过提供科学依据产生积极影响， 寻求NK细胞作为与年龄相关的神经退行性疾病的潜在免疫靶点。