BLR&D Research Career Scientist Award

蛋白质聚集是大多数或所有类型神经退行性变的基础，许多 其他年龄进行性疾病。我们已经分离和分析了非常纯的聚集体 来自阿尔茨海默氏症(AD)、帕金森氏病(PD)；线虫模型 亨廷顿病(HD)、阿尔茨海默病(AD)和帕金森病(PD)；以及AD的人类细胞培养模型。这个 构成这些聚集体的蛋白质显示出相当大的重叠；例如， 来自AD的聚集体中显著丰富的80%的蛋白质 年龄匹配的对照组，在淀粉样斑块(包含Aβ1-42)中共享且一致 和含有过度磷酸化tau的神经纤维缠结)，尽管这些 长期以来，聚集体一直被认为完全是细胞外和神经元内的， 分别进行了分析。我们最近进行了新的交联性研究，定义了这种蛋白质 调节聚集体内黏附的界面，并已筛选出其药物 在体内破坏蛋白质结合的能力。几种药物有能力减少或 慢聚合应计，其中一个(PNR502)已被证明在 AD样淀粉样变性的小鼠和线虫模型。我们目前正处于 进行定量结构-活性研究以生成 第二代药物，进一步优化了理想的药物特性。有两项专利 (退伍军人事务部和附属大学都参与)活性药物亚类的备案； 其中第一个涉及PNR502及其几个结构类似物。

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.