Microglial-Targeted Nanotherapeutics for Inhibition of Alpha-Synuclein Aggregation and Inflammation in Neurodegenerative Diseases

抑制神经退行性疾病中α-突触核蛋白聚集和炎症的小胶质细胞靶向纳米疗法

• 批准号: 9759742
• 负责人: PRABHAS V MOGHE
• 金额: $ 19.13万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9759742
• 关键词: Address; Aging; Antioxidants; Area; Attenuated; Binding; Blood Cells; Brain; Brain region; Cells; Chronic; Degradation Pathway; Dementia; Deposition; Development; Disease; Environment; Foundations; Gatekeeping; Genetic; In Vitro; Inflammation; Inflammatory; Lewy Body Dementia; Mediating; Membrane; Microglia; Molecular Target; Mutate; Nanotechnology; Nerve Degeneration; Neurodegenerative Disorders; Outcome Study; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Pathway interactions; Periodicity; Phagocytosis; Pharmacology; Phenotype; Play; Population; Reporting; Research; Role; Site; Substantia nigra structure; Therapeutic; Toxic effect; age related neurodegeneration; alpha synuclein; amphiphilicity; base; brain cell; cell type; cytokine; design; dopaminergic neuron; extracellular; in vivo; innovation; macromolecule; monomer; nanoparticle; nanotherapeutic; neuroinflammation; neuron loss; neuropathology; neurotoxic; neurotoxicity; novel; novel therapeutics; particle; prevent; protein aggregation; receptor; receptor binding; recruit; response; scavenger receptor; synuclein; synucleinopathy; targeted delivery; trafficking; uptake

PROJECT SUMMARY This project aims to design an innovative nanotherapeutic for treatment of synucleinopathies such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), or dementia with Lewy bodies (DLB). These age-related neurodegenerative diseases are characterized by the deposition and aggregation of the protein alpha-synuclein (ASYN). Chronic and excessive ASYN accumulation can cause the recruitment of microglia cells that play the important role of clearance of ASYN. Sustained activation of microglia compromises the normal degradation pathways of ASYN, leading to a cycle of internal ASYN aggregation and neuroinflammation. Thus targeting microglial cells is a potentially viable approach for treating ASYN related neurodegeneration. The central hypothesis is that that by regulating ASYN interactions with microglial receptors, intracellular aggregation of ASYN can be inhibited, and that the progression of synucleinopathy can be halted. We aim to develop nanotherapeutics by designing synthetic nanoparticles (NPs) composed of amphiphilic molecules that can molecularly target specific microglial scavenger receptors (SRs). SRs mediate the uptake of ASYN and also catalyze ASYN oligomerization. In Aim 1, we propose a novel design for the NPs such that the NPs can serve as binding partners to SRs along with ASYN, but once internalized within microglia, the active core region of these nanoparticles will be exposed, disrupting intracellular aggregation of ASYN. In Aim 2, we will also investigate the efficacy of delivering an antioxidant payload to counteract microglial activation and thus ameliorate the activation of the pro-inflammatory M1 microglial phenotype. The effects of the NPs on microglial ASYN uptake and intracellular aggregation will be evaluated in vitro and in vivo. In addition to decreasing ASYN aggregation, targeting microglial activation states by suppressing the harmful effects of M1 microglia or switching activation states to the neuroprotective M2 phenotype can provide therapeutic benefits in neurodegenerative diseases. The overall outcomes from this study will help to address the critical barriers of maintaining microglial clearance of ASYN and decreasing the inflammatory effects of classically activated microglia within synucleinopathies and other neurodegenerative diseases.

项目摘要 该项目旨在设计一种创新的纳米疗法，以治疗突触核酸治疗 例如帕金森氏病（PD），帕金森氏病痴呆症（PDD）或Lewy痴呆症 身体（DLB）。这些与年龄有关的神经退行性疾病的特征是 蛋白质α-核蛋白（ASYN）的沉积和聚集。慢性和过多的Asyn 积累会引起小胶质细胞的募集，从而起着重要作用 清除Asyn。小胶质细胞的持续激活损害了正常降解 ASYN的途径，导致内部ASYN聚集和神经炎症的循环。 因此，靶向小胶质细胞是治疗ASYN相关的潜在可行方法 神经变性。中心假设是通过调节ASYN相互作用 使用小胶质细胞受体，可以抑制ASYN的细胞内聚集，并且 突触核苷的进展可以停止。 我们旨在通过设计由合成纳米颗粒（NP）来开发纳米疗法 可以分子​​靶向特定的小胶质清除剂受体（SRS）的两亲分子。 SRS介导ASYN的摄取，并催化Asyn低聚。在AIM 1中，我们建议 NP的新颖设计，使得NP可以作为与SRS的约束伙伴 Asyn，但一旦在小胶质细胞内进行内化，这些纳米颗粒的活性核心区域将 暴露，破坏ASYN的细胞内聚集。在AIM 2中，我们还将调查 提供抗氧化有效载荷以抵消小胶质激活的功效，从而 改善促炎性M1小胶质细胞表型的激活。效果 小胶质细胞摄取和细胞内聚集的NP将在体外和IN中评估 体内。除了减少ASYN聚集外，还针对小胶质细胞激活状态 抑制M1小胶质细胞或转换激活状态的有害作用 神经保护性M2表型可以在神经退行性疾病中提供治疗益处。 这项研究的总体结果将有助于解决维护的关键障碍 ASYN的小胶质清除率并减少经典激活的炎症作用 突触核苷病和其他神经退行性疾病中的小胶质细胞。

项目成果

Microglia-targeting nanotherapeutics for neurodegenerative diseases

• DOI: 10.1063/5.0013178
• 发表时间: 2020-09
• 期刊: APL Bioengineering
• 影响因子: 6
• 作者: Nanxia Zhao;Nicola L Francis;Hannah R. Calvelli;P. Moghe

Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.

• DOI: 10.1186/s40035-023-00393-7
• 发表时间: 2024-01-04
• 期刊: TRANSLATIONAL NEURODEGENERATION
• 影响因子: 12.6
• 作者: Gebril, Hoda M.;Aryasomayajula, Aravind;de Lima, Mariana Reis Nogueira;Uhrich, Kathryn E.;Moghe, Prabhas V.
• 通讯作者: Moghe, Prabhas V.