BLR&D Research Career Scientist Award

蛋白质聚集是大多数或所有类型的神经变性的基础， 其他年龄进展性疾病。我们分离并分析了非常纯的聚集体 阿尔茨海默病（AD）、帕金森病（PD）的线虫模型; 亨廷顿氏病（HD）、AD和PD;以及AD的人细胞培养模型。的 有助于这些聚集体的蛋白质显示出相当大的重叠;例如， >80%的蛋白质在来自AD的聚集体中比来自AD的聚集体中显著更丰富， 年龄匹配的对照组，在淀粉样斑块（含Aβ1-42）中共享且一致 以及在含有过度磷酸化tau的神经元缠结中），尽管这些 聚集体长期以来被认为仅仅是细胞外和神经元内的， 分别我们最近进行了新的交联研究， 介导聚集体内粘附的界面，并筛选了用于其 破坏体内蛋白质聚结的能力。几种药物有能力减少或 一个（PNR 502）已被证明可以逆转聚合， AD样淀粉样变性的小鼠和线虫模型。我们目前正在 进行定量结构-活性研究的过程，以生成 第二代药物，进一步优化所需的药物特性。两项专利 已提交（VA和附属大学参与）活性药物子集; 其中第一个涉及PNR 502及其几种结构类似物。

Protein aggregation underlies most or all types of neurodegeneration and many other age-progressive diseases. We have isolated and analyzed very pure aggregates from Alzheimer’s Disease (AD), Parkinson’s Disease (PD); nematode models of Huntington’s Disease (HD), AD, and PD; and human cell-culture models of AD. The proteins that contribute to these aggregates show considerable overlap; for example, >80% of proteins that are significantly more abundant in aggregates from AD than from age-matched controls, are shared and concordant in amyloid plaque (containing Aβ1-42) and in neurofibrillary tangles containing hyperphosphorylated tau), although these aggregates have long been thought to be exclusively extracellular and intra-neuronal, respectively. We recently performed novel cross-linking studies that defined the protein interfaces that mediate adhesion within aggregates, and have screened drugs for their ability to disrupt protein coalescence in vivo. Several drugs have the ability to reduce or slow aggregate accrual, and one (PNR502) has been shown to reverse aggregation in both mouse and nematode models of AD-like amyloidosis. We are currently in the process of performing quantitative structure-activity studies to enable the generation of 2nd-generation drugs, further optimized for desirable drug properties. Two patents have been filed (with both VA and affiliated-university participation) for subsets of active drugs; the first of these addresses PNR502 and several of its structural analogs.