Collaborative Research: How to Foil Synuclein Aggregation? Nanotechnology for Inhibition of Neurodegenerative Brain Plaques

合作研究：如何阻止突触核蛋白聚集？

• 批准号: 1803675
• 负责人: Prabhas Moghe
• 金额: $ 42.95万
• 依托单位: Rutgers University New Brunswick
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1803675&HistoricalAwards=false
• 关键词: Collaborative; Research; How; Foil; Synuclein

As a greater proportion of our society ages, the scope and severity of brain health disorders are widening. One of the serious challenges in neuroscience and aging is the progressive nerve damage that stems from excessive protein aggregation (proteins stick together and form a cluster) in the brain. Alpha-synuclein (ASYN) is a key protein whose uncontrolled aggregation is believed to be a major risk factor leading to the death of healthy neurons and causing diseases like Parkinson' disease (PD) and certain types of dementia. Under healthy conditions, immune cells in the brain attract and take-in ASYN, which is then degraded within the cell, a process referred to as "ASYN clearance." Under unhealthy conditions, the ASYN aggregates within the immune cell, which prevents degradation and leads to immune cell damage and ultimately to nerve damage. Thus the challenging goal of this project is to design a therapeutic strategy for increasing the immune cell uptake of ASYN while minimizing the potential for ASYN aggregation within the cell. The goal will be addressed using a systems-level engineering approach to design novel materials based on polymers that can help the immune cell uptake of ASYN yet interfere with ASYN aggregation within the cell. Initial studies are designed to analyze protein-receptor interactions in vitro (outside the body). These studies will then be extended to cellular and mouse models of ASYN clearance and aggregation. The highly cross-disciplinary nature of this team will inspire boundary-bridging research, education, and outreach. The educational efforts associated with this project will involve undergraduate researchers in summer experiences and lab boot-camp workshops in an REU on Cellular Bioengineering, as well as graduate and postdoctoral research experiences in diversity-expanding training programs on the campus.A major class of brain degenerative conditions is associated with excessive build up of aggregates of Alpha-synuclein (ASYN) and are referred to as "synucleinopathies." ASYN is one of the disordered proteins whose dysregulated degradation and clearance can lead to high levels of oligomers, which can be released and can cause neurotoxicity. The objective of this project is to design novel nanoscale materials with intrinsic therapeutic activity to advance a systems-level engineering approach to address the coupled processes of ASYN uptake/clearance (which needs to be increased) and ASYN aggregation (which needs to be disrupted). The key intellectual innovation is the design of polymers that show tunable affinity to scavenger receptor proteins and the combination of such as ligands within dual-action nanoparticles (NPs). The shell ligands will act as nano-chaperones for ASYN binding and uptake into immune cells (microglia), while the core ligands will serve to disrupt the scavenger receptor templating that leads to self-aggregation of ASYN. The research plan is arranged under three aims: 1) To elucidate the key receptor phenomena that trigger enhanced oligomerization of ASYN following its uptake in microglia, thus developing a rational basis for designing counter-ligands to disrupt these interactions; 2) To design synthetic counter-ligands, which disrupt ASYN intracellular oligomerization while enabling ASYN uptake and clearance, thus developing a rational design for independently functional NPs; and 3) To evaluate the dual ability of AM (amphiphilic macromolecules)-based NPs to promote ASYN clearance while inhibiting ASYN aggregation within a pilot synunucleinopathy model for a "dyanamic" brain environment, thus identifying the NP's role in engineering the rescue kinetics from ASYN aggregation. These aims are designing to test the hypothesis that nanotechnology-mediated microglial dynamics of ASYN will reduce ASYN-induced neuropathology and toxicity in vivo, which may have significant implications for treatment of synucleinopathies, for which there are currently no disease modifying therapies.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

随着我们社会中越来越多的人老龄化，大脑健康障碍的范围和严重程度正在扩大。 神经科学和衰老的严重挑战之一是大脑中过度的蛋白质聚集（蛋白质粘在一起形成簇）引起的进行性神经损伤。 α-突触核蛋白（ASYN）是一种关键蛋白质，其不受控制的聚集被认为是导致健康神经元死亡并引起帕金森病（PD）和某些类型痴呆症等疾病的主要风险因素。 在健康的条件下，大脑中的免疫细胞吸引并吸收ASYN，然后在细胞内降解，这一过程被称为“ASYN清除”。“在不健康的条件下，ASYN在免疫细胞内聚集，这会阻止降解并导致免疫细胞损伤，最终导致神经损伤。 因此，该项目的挑战性目标是设计一种治疗策略，用于增加ASYN的免疫细胞摄取，同时最大限度地减少ASYN在细胞内聚集的可能性。 该目标将使用系统级工程方法来设计基于聚合物的新型材料，这些材料可以帮助免疫细胞摄取ASYN，但干扰细胞内的ASYN聚集。 最初的研究旨在分析体外（体外）蛋白质-受体相互作用。 然后，这些研究将扩展到ASYN清除和聚集的细胞和小鼠模型。 该团队的高度跨学科性质将激发边界桥接研究，教育和推广。 与该项目相关的教育工作将涉及本科生研究人员在夏季的经验和实验室训练营研讨会在一个REU细胞生物工程，以及研究生和博士后的研究经验，在校园里的多样性扩展培训计划。一个主要类别的大脑退行性疾病是与过度积累的聚集体的α-突触核蛋白（ASYN），被称为“突触核蛋白病。“ASYN是一种紊乱的蛋白质，其失调的降解和清除可导致高水平的低聚物，这些低聚物可被释放并可导致神经毒性。 该项目的目标是设计具有内在治疗活性的新型纳米材料，以推进系统级工程方法，以解决ASYN摄取/清除（需要增加）和ASYN聚集（需要中断）的耦合过程。 关键的智力创新是设计对清道夫受体蛋白具有可调亲和力的聚合物，以及在双作用纳米颗粒（NP）内结合配体。壳配体将充当ASYN结合和摄取到免疫细胞（小胶质细胞）中的纳米分子伴侣，而核心配体将用于破坏导致ASYN自聚集的清道夫受体模板。 本研究计划安排在三个目标下：1）阐明ASYN在小胶质细胞中摄取后引发增强的寡聚化的关键受体现象，从而为设计反配体以破坏这些相互作用提供合理的基础; 2）设计合成的反配体，其破坏ASYN细胞内寡聚化，同时使ASYN摄取和清除成为可能，从而为独立功能的NP开发合理的设计;评价AM的双重能力在“动力学”脑环境的试验性突触核蛋白病模型中，从而鉴定NP在工程化ASYN聚集的拯救动力学中的作用。 这些目的旨在检验以下假设：纳米技术介导的ASYN小胶质细胞动力学将减少ASYN诱导的体内神经病理学和毒性，这可能对治疗突触核蛋白病具有重要意义，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查进行评估，被认为值得支持的搜索.

项目成果

CD36‐Binding Amphiphilic Nanoparticles for Attenuation of α‐Synuclein‐Induced Microglial Activation

CD36 — 结合两亲性纳米颗粒，用于减弱 α — 突触核蛋白 — 诱导的小胶质细胞激活

• DOI: 10.1002/anbr.202100120
• 发表时间: 2022
• 期刊: Advanced NanoBiomed Research
• 影响因子: 3.4
• 作者: Zhao, Nanxia;Francis, Nicola L.;Song, Shuang;Kholodovych, Vladyslav;Calvelli, Hannah R.;Hoop, Cody L.;Pang, Zhiping P.;Baum, Jean;Uhrich, Kathryn E.;Moghe, Prabhas V.
• 通讯作者: Moghe, Prabhas V.

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