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

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

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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的基础其他年龄疾病。我们已经孤立和分析了非常纯的聚集体来自阿尔茨海默氏病（AD），帕金森氏病（PD）；线虫模型亨廷顿氏病（HD），AD和PD；和AD的人类细胞培养模型。这促成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AD中的蛋白质比来自年龄匹配的对照，在淀粉样斑块中共享和一致（包含Aβ1-42）在含有磷酸化tau的神经纤维缠结中，尽管这些长期以来，聚集体被认为是细胞外和神经内的，分别。我们最近进行了新的交联研究，以定义蛋白质介导汇总广告的界面，并为其筛选了药物在体内破坏蛋白质聚结的能力。几种药物具有减少或缓慢的聚集体和一个（PNR502）已被证明在 AD样淀粉样变性的小鼠和线虫模型。我们目前正在进行定量结构活性研究的过程以使能够产生第二代药物，进一步针对理想的药物特性进行了优化。有两项专利为活性药物的亚群提交（VA和会员大学的参与）；这些第一个介绍了PNR502及其几种结构类似物。