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.

项目概要 该项目旨在设计一种用于治疗突触核蛋白病的创新纳米疗法 例如帕金森病 (PD)、帕金森病痴呆 (PDD) 或路易痴呆 机构（DLB）。这些与年龄相关的神经退行性疾病的特点是 蛋白质α-突触核蛋白（ASYN）的沉积和聚集。慢性且过度的 ASYN 积累会导致小胶质细胞的募集，这些细胞在 ASYN 的清除。小胶质细胞的持续激活会损害正常降解 ASYN 通路，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 交互 与小胶质细胞受体结合，可以抑制 ASYN 的细胞内聚集，并且 可以阻止突触核蛋白病的进展。 我们的目标是通过设计由以下物质组成的合成纳米颗粒（NP）来开发纳米疗法： 可以分子​​靶向特定小胶质细胞清道夫受体（SR）的两亲性分子。 SR 介导 ASYN 的摄取并催化 ASYN 寡聚化。在目标 1 中，我们建议 NP 的新颖设计使得 NP 可以作为 SR 的结合伙伴 ASYN，但一旦内化到小胶质细胞内，这些纳米粒子的活性核心区域将 暴露，破坏 ASYN 的细胞内聚集。在目标 2 中，我们还将调查 传递抗氧化剂有效负载以抵消小胶质细胞活化的功效，从而 改善促炎 M1 小胶质细胞表型的激活。的影响 将在体外和体内评估 NP 对小胶质细胞 ASYN 摄取和细胞内聚集的影响 体内。除了减少 ASYN 聚集外，还通过以下方式针对小胶质细胞激活状态： 抑制 M1 小胶质细胞的有害影响或将激活状态切换到 神经保护性 M2 表型可以为神经退行性疾病提供治疗益处。 这项研究的总体结果将有助于解决维持生命的关键障碍 小胶质细胞清除 ASYN 并减少经典激活的炎症效应 突触核蛋白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.