PATHOLOGY

病理

基本信息

批准号：
7638111
负责人：
Stephen J. DeArmond
金额：
$ 20.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7638111
关键词：
Aging Animals Autopsy Axonal Transport Biology Biopsy Brain Brain region Cause of Death Cavia Clinical Data Codon Nucleotides Combined Modality Therapy Creutzfeldt-Jakob Syndrome Data Databases Dendrites Detection Development Diagnosis Diagnostic Procedure Disease Drug Delivery Systems Early Diagnosis Enrollment Evaluation Freezing Gene Mutation Gliosis Goals Golgi Apparatus Hamsters Immunohistochemistry Knowledge Laboratory Research Methods Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neurological status Neurons Oral Organ Pathogenesis Pathology Patients Pattern Polymorphism Analysis PrP PrPSc Proteins Preparation Prion Diseases Prions Publications Quinacrine Research Personnel Residual state Resources Sampling Scrapie Services Signal Pathway Silver Staining Site Skeletal Muscle Spleen Staging Staining method Stains Structure Synapses Synaptophysin Thalamic structure Western Blotting effective therapy improved inhibitor/antagonist neuronal cell body neuropathology notch protein novel therapeutics presynaptic prevent programs response secretase

项目摘要

X/Partial The Neuropathology Core (NP Core) is a component of the DeArmond Neuropathology Research Laboratory (NRL). NP Core directed by S. DeArmond is part of a remarkably productive collaboration with Stanley Prusiner for the past 24 years. The NP Core is particularly enthusiastic about this PPG proposal because of the results of a drug trial recently completed by the NRL in which PrPSc formation, axonal transport of PrPSc and dendrite degeneration were prevented by oral doses of a y-secretase inhibitor plus quinacrine. Residual PrPSc remained in brain regions that were the first to become infected by inoculation with prions and had accumulated high levels of PrPSc before treatment was begun. Such sites were niduses for restart of PrPSc formation. The NP Core will fulfill three basic functions: First, it will perform full autopsies on CJD patients and related controls. The basic goals are to verify the diagnosis and the immediate cause of death, and to dissect samples from the CNS, muscle, visceral organs and other sites as needed in Project 3. Second, quantitative morphological and neurochemical analysis of dissected brain regions during the course of CJD and other human prion diseases transmitted to guinea pigs and transgenic (Tg) mice will correlate the kinetics of PrPSc formation and accumulation in each brain region with the vacuolation, dendrite and presynaptic bouton degeneration; reactive astrocytic gliosis; activation of microglia; and nerve cell loss. These data will be correlated with non-invasive tests for PrPSc in blood and other systemic sites. The rodent models of human prion diseases will also allow us to test whether non-invasive peripheral measurements of abnormal PrPs or other proteins predict and correlate well with beneficial effects of emerging treatments of prion diseases that clear PrPSc from the brain and prevent neurodegeneration. Third, neuropathological verification of prion disease in hamsters, wild-type mice and Tg mice will be performed for Projects 1 and 2, which focus on the structure of PrPSc.

X/部分神经病理学核心（NP核心）是Dearmond神经病理研究实验室的组成部分（NRL）。 S. Dearmond执导的NP Core是与Stanley的富有成效合作的一部分过去24年中的Prusiner。 NP核心对此PPG提案特别热情 NRL最近完成了一项药物试验的结果，其中PRPSC形成，PRPSC的轴突运输通过口服Y-分泌酶抑制剂加奎诺克林的口服剂量，预防了树突变性。残留 PRPSC仍然留在大脑区域，这些区域是第一个因接种王室而感染的，并且在开始治疗之前，积累了高水平的PRPSC。这样的站点是重新启动PRPSC的Niduses 形成。 NP核心将履行三个基本功能：首先，它将对CJD患者进行完整尸检和相关控件。基本目标是验证诊断和直接死亡原因，并根据项目3中的需要，从中枢神经系统，肌肉，内脏器官和其他地点剖析样品。其次， CJD过程中解剖的大脑区域的定量形态和神经化学分析传播到豚鼠和转基因（TG）小鼠的其他人类病毒疾病将使该疾病相关通过空泡，树突和突触前的BOUTON变性；反应性星形胶质神经胶质病；小胶质细胞的激活；和神经细胞丧失。这些数据将与血液和其他全身部位中PRPSC的非侵入性测试相关。啮齿动物人类prion疾病的模型还将使我们能够测试是否非侵入性外围测量异常的PRP或其他蛋白质预测并与新兴治疗的有益作用很好地相关病毒疾病可以从大脑中清除PRPSC并预防神经退行性。第三，神经病理学将对项目1和2进行仓鼠，野生型小鼠和TG小鼠的幼虫疾病的验证专注于PRPSC的结构。