Microglial RGS10 as a therapeutic target for Lewy body diseases

小胶质细胞 RGS10 作为路易体疾病的治疗靶点

• 批准号: 10041109
• 负责人: Jae Kyung Lee
• 金额: $ 42.94万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10041109
• 关键词: Aging; Alzheimer' s Disease; Amyloid Fibrils; Amyloid beta-Protein; Antibodies; Brain; Cations; Cells; Charge; Chronic; Coculture Techniques; Dementia; Electrostatics; Energy Metabolism; Exhibits; GTP-Binding Protein Regulators; GTP-Binding Proteins; Genes; Glycolic-Lactic Acid Polyester; Health; Hippocampus (Brain); Histologic; Homeostasis; Human; Hydrophobicity; Immune; Immunohistochemistry; Immunologic Surveillance; Inflammaging; Inflammation; Injections; Knockout Mice; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Metabolic; Metabolic Diseases; Metabolism; Microglia; Modeling; Monoclonal Antibodies; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phenotype; Plasmids; Play; Polymers; Predisposition; Proteins; Publishing; Recovery of Function; Risk Factors; Role; Scheme; Signaling Protein; Specificity; Surface; System; Treatment Efficacy; Universities; Work; age related; age related neurodegeneration; alpha synuclein; amphiphilicity; central nervous system injury; clinically relevant; combinatorial; dementia risk; energy balance; in vitro Model; in vivo; innovation; knock-down; mouse model; nanocarrier; nanoparticle; nanotherapeutic; neuroinflammation; neuron loss; neuropathology; neuroprotection; neurotoxicity; novel; nucleic acid-based therapeutics; protein aggregation; synucleinopathy; therapeutic evaluation; therapeutic target

SUMMARY Aging-related inflammation and metabolic disorders, including Alzheimer's disease (AD), Lewy body dementia (LBD), and Dementia with Lewy bodies (DLB), constitute serious threats to human health as they are risk factors for dementia. Microglia play a critical role in immune surveillance in the CNS, clearing abnormal protein aggregates, and maintaining energy balance and metabolism. However, microglia undergo phenotypic changes during neurodegenerative disorders and contribute to neurodegenerative diseases. Therefore, we may be able to harness the activity of microglia and restore metabolic homeostasis as an effective therapeutic for age-related neurodegenerative disorders. The objective of this proposal is to develop a microglia-specific nanotherapeutic for amyloid fibrils-induced neurodegeneration composed of an antibody targeting to microglia (Tmem119) and plasmid encoding regulator of G-protein signaling 10 (pRGS10). RGS10 is a homeostatic protein in microglia and its level is significantly decreased with chronic inflammation and aging. Our preliminary study demonstrated that RGS10 enhances phagocytosis of abnormally aggregated proteins including fibrillar β- amyloid (fAβ) and α-synuclein (α-syn). We hypothesize that enriching RGS10 levels through microglia-specific nanoparticles carrying pRGS10 may restore microglial homeostasis, enhance amyloid fibril clearance, and provide neuroprotection against amyloid-fibril-induced neuronal death. We will utilize two innovative approaches: a novel cationic amphiphilic co-polymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP): and a preformed fibril (PFF) α-syn mouse model of Lewy body diseases (PFF mouse model) to determine if microglial RGS10 is neuroprotective. In Aim 1, we will conjugate anti-Tmem119 mAb to the surface of PgP (Tmem-PgP), formulate Tmem-PgP/pRGS10 nanoparticles and evaluate target-specificity and neuroprotection in a primary neuron/microglia co-culture system. In Aim 2, we will demonstrate the therapeutic efficacy of Tmem-PgP/pRGS10 in the PFF mouse model. The completion of this study will elucidate the role of RGS10 in maintaining microglia homeostatic conditions and how we may utilize RGS10 as a therapeutic target for amyloid fibril-associated neurodegenerative diseases.

摘要 与衰老相关的炎症和代谢紊乱，包括阿尔茨海默病(AD)、路易体痴呆 (LBD)和路易体痴呆(DLB)对人类健康构成严重威胁，因为它们是危险的 导致痴呆症的因素。小胶质细胞在中枢神经系统的免疫监视中发挥关键作用，清除异常蛋白 聚集，维持能量平衡和新陈代谢。然而，小胶质细胞经历了表型 在神经退行性疾病期间的变化，并导致神经退行性疾病。因此，我们 可能能够利用小胶质细胞的活性，恢复代谢稳态，作为一种有效的治疗方法 治疗与年龄相关的神经退行性疾病。 这项建议的目的是 开发一种小胶质细胞特异性的 抗小胶质细胞抗体纳米治疗淀粉样蛋白诱导的神经变性 (Tem119)和编码G蛋白信号转导调节因子10的质粒(PRGS10)。 RGS10是一种动态平衡 小胶质细胞中的蛋白及其水平随着慢性炎症和年龄的增长而显著降低。我们的预赛 研究表明，RGS10增强了对异常聚集的蛋白质的吞噬作用，包括纤维状β- 淀粉样蛋白(FAβ)和α-突触核蛋白(α-SYN)。我们假设，通过小胶质细胞特异的方式丰富RGS10水平 携带pRGS10的纳米颗粒可以恢复小胶质细胞的稳态，增强淀粉样蛋白纤维的清除，以及 提供神经保护，防止淀粉样原纤维诱导的神经元死亡。我们将利用两个创新的 方法：一种新型的阳离子两亲性共聚物，聚丙交酯-乙交酯-接枝-聚乙烯亚胺(PGP)： 和预成型纤维蛋白(Pff)α-syn小鼠路易体疾病模型(pff小鼠模型)以确定 小胶质细胞RGS10具有神经保护作用。在目标1中，我们将抗Tem119单抗偶联到Pgp表面 (TMEM-PGP)，制备TMEM-PGP/pRGS10纳米粒，并评价靶向性和神经保护作用 在原代神经元/小胶质细胞共培养系统中。在目标2中，我们将演示 TMEM-PGP/pRGS10在PFF小鼠模型中表达。这项研究的完成将阐明RGS10在 维持小胶质细胞的动态平衡状态以及我们如何利用RGS10作为治疗靶点 淀粉样原纤维相关的神经退行性疾病。