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BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
10293555
负责人：
Robert Joseph Shmookler Reis
金额：
--
依托单位：
CENTRAL ARKANSAS VETERANS HLTHCARE SYS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-10-01 至 2026-09-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10293555
关键词：
Address Adhesions Affinity Age Age Distribution Age-Years Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Amyloidosis Award Binding Binding Proteins Bioinformatics Brain Cachexia Caenorhabditis elegans Cell Aging Cell Culture Techniques Cell model Cells Chemistry Chinese population Chronic Data Disease Drug Screening Drug Targeting Environmental Risk Factor Etiology Exposure to Family Generations Genes Genetic Genetic Variation Healthcare Healthcare Systems Heart Diseases Hippocampus (Brain)Human Huntington Disease Hypertension Incidence Intervention Laboratories Legal patent Libraries Link Location Malignant neoplasm of prostate Mammalian Genetics Mediating Modeling Molecular Molecular Genetics Multiple Myeloma Mus Muscular Atrophy Nematoda Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neuropathy Oncogenic Orthologous Gene Oxidation-Reduction Oxidative Stress Oxides Paper Parkinson Disease Pathology Peptides Pharmaceutical Preparations Phosphorylated Peptide Play Post-Translational Protein Processing Postmenopause Prevention Process Progressive Disease Property Proteins Publishing Rare Diseases Reagent Reporting Research Research Priority Resistance Risk Factors Role Scientist Senile Plaques Signal Pathway Specificity Spinal Cord Stress Structure Testing Time Traumatic Brain Injury Universities Veterans Woman age related aging population analog bone loss career cohesion crosslink cytotoxicity design disorder risk extracellular gene network high risk homologous recombination hyperphosphorylated tau improved in silico in vivo in vivo evaluation inhibitor insight link protein malignant breast neoplasm military veteran neurological pathology novel novel strategies novel therapeutics potency testing prevent protein aggregation protein protein interaction relating to nervous system screening senescence

项目摘要

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.

蛋白质聚集是大多数或所有类型的神经变性和许多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)；线虫模型亨廷顿舞蹈病 (HD)、AD 和 PD；以及 AD 的人类细胞培养模型。这有助于这些聚集的蛋白质显示出相当大的重叠；例如， >80% 的蛋白质在 AD 中的聚集体中含量显着高于来自 AD 的蛋白质年龄匹配的对照，淀粉样斑块（含有 Aβ1-42）是共享且一致的以及含有过度磷酸化 tau 的神经原纤维缠结），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。我们最近进行了新颖的交联研究，定义了蛋白质介导聚集体内粘附的界面，并筛选了其药物破坏体内蛋白质聚结的能力。有几种药物能够减少或聚合累积缓慢，其中一个 (PNR502) 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，进一步优化所需的药物特性。拥有两项专利活性药物子集已备案（VA 和附属大学参与）；第一个地址是 PNR502 及其几个结构类似物。