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

随着我们社会老龄化的比例越来越大，大脑健康疾病的范围和严重性正在扩大。神经科学和老龄化领域的一个严重挑战是大脑中蛋白质过度聚集(蛋白质粘在一起并形成簇)导致的进行性神经损伤。α-突触核蛋白(ASYN)是一种关键蛋白，其不受控制的聚集被认为是导致健康神经元死亡的主要风险因素，并导致帕金森病(PD)和某些类型的痴呆症等疾病。在健康条件下，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聚集在免疫细胞内，防止降解，导致免疫细胞损伤，最终导致神经损伤。因此，该项目具有挑战性的目标是设计一种治疗策略，以增加免疫细胞对ASYN的摄取，同时将ASYN在细胞内聚集的可能性降至最低。这一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，这种聚合物可以帮助免疫细胞摄取ASYN，同时干扰ASYN在细胞内的聚集。最初的研究旨在分析体外(体外)蛋白质-受体的相互作用。这些研究随后将扩展到ASYN清除和聚集的细胞和小鼠模型。这个团队的高度跨学科性质将激励跨越边界的研究、教育和外展。与该项目相关的教育努力将包括本科生研究人员在REU的暑期体验和细胞生物工程实验室训练营研讨会，以及在校园扩大多样性培训计划中的研究生和博士后研究经验。大脑退行性疾病的一大类与α-突触核蛋白(ASYN)聚集体过度积累有关，被称为“突触核病”。ASYN是一种无序蛋白质，其不受调控的降解和清除可导致高水平的寡聚体，这些寡聚体可以释放并导致神经毒性。该项目的目标是设计具有内在治疗活性的新型纳米材料，以推进系统水平的工程方法，以解决ASYN摄取/清除(需要增加)和ASYN聚集(需要破坏)的耦合过程。关键的智力创新是设计出对清道夫受体蛋白具有可调亲和力的聚合物，并将这些配体结合到双重作用纳米颗粒(NPs)中。壳配体将作为免疫细胞(小胶质细胞)结合和摄取ASYN的纳米伴侣，而核心配体将破坏导致ASYN自我聚集的清道夫受体模板。该研究计划安排在三个目标下：1)阐明ASYN在小胶质细胞摄取后触发ASYN增强寡聚化的关键受体现象，从而为设计反配体破坏这些相互作用提供合理的基础；2)设计合成的反配体，它破坏ASYN细胞内的寡聚作用，同时使ASYN能够摄取和清除，从而开发出独立功能的NPs的合理设计；以及3)评估基于AM(两亲性大分子)的NPs的双重能力，在一个试验性共核病模型中促进ASYN的清除，同时抑制ASYN的聚集，从而确定NP在工程上从ASYN聚集中拯救动力学的作用。这些目的是为了测试这样一种假设，即纳米技术介导的ASYN的小胶质细胞动力学将减少ASYN诱导的神经病理和体内毒性，这可能对目前尚无疾病修饰疗法的联合核病的治疗具有重大影响。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.