BLR&D Research Career Scientist Award
BLR
基本信息
- 批准号:10293555
- 负责人:
- 金额:--
- 依托单位:
- 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:
- 关键词:AddressAdhesionsAffinityAgeAge DistributionAge-YearsAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease riskAmyloidosisAwardBindingBinding ProteinsBioinformaticsBrainCachexiaCaenorhabditis elegansCell AgingCell Culture TechniquesCell modelCellsChemistryChinese populationChronicDataDiseaseDrug ScreeningDrug TargetingEnvironmental Risk FactorEtiologyExposure toFamilyGenerationsGenesGeneticGenetic VariationHealthcareHealthcare SystemsHeart DiseasesHippocampus (Brain)HumanHuntington DiseaseHypertensionIncidenceInterventionLaboratoriesLegal patentLibrariesLinkLocationMalignant neoplasm of prostateMammalian GeneticsMediatingModelingMolecularMolecular GeneticsMultiple MyelomaMusMuscular AtrophyNematodaNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuropathyOncogenicOrthologous GeneOxidation-ReductionOxidative StressOxidesPaperParkinson DiseasePathologyPeptidesPharmaceutical PreparationsPhosphorylated PeptidePlayPost-Translational Protein ProcessingPostmenopausePreventionProcessProgressive DiseasePropertyProteinsPublishingRare DiseasesReagentReportingResearchResearch PriorityResistanceRisk FactorsRoleScientistSenile PlaquesSignal PathwaySpecificitySpinal CordStressStructureTestingTimeTraumatic Brain InjuryUniversitiesVeteransWomanage relatedaging populationanalogbone losscareercohesioncrosslinkcytotoxicitydesigndisorder riskextracellulargene networkhigh riskhomologous recombinationhyperphosphorylated tauimprovedin silicoin vivoin vivo evaluationinhibitorinsightlink proteinmalignant breast neoplasmmilitary veteranneurological pathologynovelnovel strategiesnovel therapeuticspotency testingpreventprotein aggregationprotein protein interactionrelating to nervous systemscreeningsenescence
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Robert Joseph Shmookler Reis其他文献
Robert Joseph Shmookler Reis的其他文献
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{{ truncateString('Robert Joseph Shmookler Reis', 18)}}的其他基金
Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration
神经变性中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
8971964 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration
神经变性中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
8803314 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Analysis and therapy of age-dependent proteostasis failure in neurodegeneration
神经退行性变中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
10474260 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration
神经变性中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
8443076 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Analysis and Therapy of Age-Dependent Proteostasis Failure in Neurodegeneration
神经变性中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
8666527 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Analysis and therapy of age-dependent proteostasis failure in neurodegeneration
神经退行性变中年龄依赖性蛋白质稳态失败的分析和治疗
- 批准号:
10082413 - 财政年份:2013
- 资助金额:
-- - 项目类别:
GENES AFFECTING METABOLISM AND LONGEVITY IN C. ELEGANS
影响线虫新陈代谢和寿命的基因
- 批准号:
7388808 - 财政年份:2007
- 资助金额:
-- - 项目类别:
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