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

随着我们社会中越来越多的人老龄化，大脑健康失调的范围和严重程度正在扩大。神经科学和衰老面临的严峻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）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和引起帕金森病（PD）和某些类型痴呆等疾病的主要危险因素。在健康状况下，大脑中的免疫细胞会吸引并吸收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，阻止降解，导致免疫细胞损伤，最终导致神经损伤。因此，本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，同时最大限度地减少细胞内ASYN聚集的可能性。该目标将采用系统级工程方法来设计基于聚合物的新型材料，这种材料可以帮助免疫细胞摄取ASYN，同时干扰细胞内的ASYN聚集。最初的研究旨在分析体外（体外）蛋白质受体的相互作用。然后，这些研究将扩展到细胞和小鼠模型的asynn清除和聚集。这个团队的高度跨学科性质将激发跨界研究、教育和推广。与此项目相关的教育工作将涉及到本科研究人员的暑期体验和REU细胞生物工程实验室训练营研讨会，以及研究生和博士后在校园多样性扩展培训项目中的研究经验。一类主要的脑退行性疾病与α -突触核蛋白（ASYN）聚集体的过度积聚有关，被称为“突触核蛋白病”。ASYN是一种无序蛋白，其降解和清除失调可导致高水平的低聚物，这些低聚物可被释放并引起神经毒性。该项目的目标是设计具有内在治疗活性的新型纳米级材料，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（需要破坏）的耦合过程。关键的智力创新是聚合物的设计，这些聚合物对清道夫受体蛋白具有可调节的亲和力，并在双作用纳米颗粒（NPs）中结合配体。壳配体将作为纳米伴侣结合并摄取到免疫细胞（小胶质细胞），而核心配体将破坏导致ASYN自聚集的清道夫受体模板。本研究计划有三个目标：1)阐明小胶质细胞摄取ASYN后引发其寡聚化增强的关键受体现象，从而为设计反配体破坏这些相互作用提供合理基础；2)设计合成反配体，在破坏细胞内ASYN寡聚的同时，使其能够摄取和清除，从而合理设计独立功能的NPs；3)在“动态”脑环境中试联核病模型中，评估基于AM（两亲性大分子）的NP促进ASYN清除和抑制ASYN聚集的双重能力，从而确定NP在从ASYN聚集中修复动力学的工程作用。这些目标旨在验证纳米技术介导的asynn小胶质动力学将减少asynn诱导的神经病理和体内毒性的假设，这可能对突触核蛋白病的治疗有重要意义，目前还没有疾病修饰疗法。该奖项反映了美国国家科学基金会的法定使命，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.