The Hieachy of Factors Causing neurodegeneration in Prion Diseases

导致朊病毒病神经变性的因素层次

• 批准号: 7903485
• 负责人: Stephen J. DeArmond
• 金额: $ 14.55万
• 依托单位: MC LAUGHLIN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7903485
• 关键词: Accounting; Address; Adopted; Alzheimer' s Disease; Animal Model; Astrocytes; Atrophic; Biological; Brain; Cell Death; Cell membrane; Clinical; Collaborations; Critiques; Data; Databases; Dendrites; Disease; Drug Combinations; Event; Extracellular Domain; FVB Mouse; Future; Ganglioside GM1; Gene Expression; Gene Expression Profile; Genes; Genetic; Gliosis; Global Change; Glycolipids; Goals; Golgi Apparatus; Image; Immunohistochemistry; In Vitro; Infection; Institutes; Interneurons; Knockout Mice; Knowledge; Learning; Link; Lysosomes; Membrane; Microglia; Modeling; Molecular; Mono-S; Mus; Mutate; Natural regeneration; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oligodendroglia; Oral; Other Genetics; Pathway interactions; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Play; PrP; PrPSc Proteins; Predisposition; Prion Diseases; Prions; Process; Quinacrine; Recovery; Regulator Genes; Relative (related person); Research Personnel; Resistance; Role; Scrapie; Signal Pathway; Silver Staining; Staging; Synapses; System; Systems Analysis; Technology; Testing; Thalamic structure; Time; Transgenic Organisms; Uncertainty; Variant; base; excitatory neuron; experience; inhibitor/antagonist; mouse model; neocortical; neuron loss; neuropathology; notch protein; prevent; programs; research study; secretase; skills; success; treatment effect

Our revisions of Project 4 are adapted to the results of our first drug trials with the g-secretase inhibitor (GSI), LY-411,575, and the Reviewer1 critiques. The focus of our first version of Project 4 was to expand on our discovery that activation of the Notch-1 represser signaling pathway links rPrPSc accumulation in synaptic regions with early occurring dendritic atrophy. The Reviewers doubted we could do the experiments in mature prion-infected brain spheres as we proposed and objected to our focus on the pathogenic role of rPrPSc ignoring other potentially pathogenic PrP molecules including tmPrP that adopts a transmembrane topology, GPI-anchorless PrP(GPI0/0), and PrP(P101L) that cause neurodegeneration without rPrPSc. Since the submission of the first proposal we found that oral GSI plus quinacrine (Q) therapy decreased rPrPSc levels in brain by 90%, prevented ~50% of the expected dendritic atrophy and loss, but had equivocal effects on reactive microgliomatosis and reactive astrocytic gliosis. Although the benefits of that combination of drugs were the best ever achieved with an animal model of scrapie, the incompleteness of the effects of treatment argued that many other neurodegenerative factors were not accounted for. For these reasons the overall aim of the revised proposal is to organize the multiple factors causing neurodegeneration and preventing recovery during prion diseases into a hierarchical or ranked order of importance. To accomplish this, 5 Specific Aims are proposed to address both global changes in the brain while still addressing specific critical issues. Aim #1 addresses our data-based hypothesis that rPrPSc is the primary cause of neurodegeneration by testing the hypothesis that it begins the process of Notch-1 activation, which leads to dendritic atrophy. Aim #2 uses multiple transgenic (Tg) mice constructed in Stanley Prusiner's Lab that exclusively express anchorless PrP, Tg(PrP GPI0/0); 95% transmembrane PrP, Tg(SHaPrP KH-¿II); 100% GPI-anchored PrPc, Tg(SHaPrP DSTE); and Tg(GSS P101L) to test the relative contribution of each pathogenic PrP form to early occurring synaptic degeneration and late occurring neuronal loss in scrapie- type prion disease. Aim #3 tests the hypothesis that inhibitory interneurons are more vulnerable than excitatory neurons during scrapie. Aim #4 uses the unique expertise of Leroy Hood's Institute to construct gene regulatory networks that will compare variations in neocortical and thalamic transcriptomes in uninfected control mice, RML prion infected mice, and RML infected mice treated with dual GSI + Q therapy. Our goal is to learn which functional gene pathways are changed with infection and which of those are corrected or not corrected by treatment. Aim #5 is to continue to develop and use a mature infectable brains sphere to test our hypotheses.

我们对项目4的修订适应了我们使用G-分泌酶抑制剂进行的首次药物试验的结果 （GSI），LY-411,575和Reviewer1 Criverques。我们第一个项目4的重点是扩展 我们发现Notch-1复制途径的激活链接RPRPSC在突触中的积累 具有早期发生树突状萎缩的区域。审稿人怀疑我们可以在 正如我们提出的那样，成熟的原始脑球形呈现，并反对我们关注的致病作用 RPRPSC忽略了采用跨膜的其他潜在病原PRP分子，包括TMPRP 拓扑，GPI无锚PRP（GPI0/0）和无RPRPSC的神经变性的PRP（P101L）。自从 提交第一个提案的提交我们发现口服GSI加奎诺克（Q）治疗降低了RPRPSC 大脑中的水平达到90％，预期的预期树突状萎缩和损失的50％，但具有等效的影响 反应性的微胶质瘤病和反应性星形胶质神经胶质病。尽管该组合的好处 毒品是有史以来最好的动物模型，这是有史以来最佳的毒品，这是不完整的影响 治疗认为未考虑许多其他神经退行性因素。由于这些原因 修订的建议的总体目的是组织导致神经变性的多个因素 防止prion病期间的恢复到层次结构或排名的重要性顺序。完成 提出了5个具体目标来解决大脑的两个全球变化，同时仍在解决特定的问题 关键问题。 AIM＃1解决了我们基于数据的假设，即RPRPSC是 神经变性通过检验以下假设，即它开始了Notch-1激活过程，这导致 树突状萎缩。 AIM＃2使用Stanley Prusiner实验室中构建的多个转基因（TG）小鼠 独家表达无锚prp，TG（PRP GPI0/0）; 95％跨膜PRP，TG（shaprp kh-€ii）; 100％ GPI锚定PRPC，TG（SHAPRP DSTE）;和TG（GSS P101L）测试每个的相对贡献 致病性PRP形式为早期发生的突触变性，并在crapie-中发生神经元丧失 类型prion病。 AIM＃3检验了抑制性中间神经元的假设比 抓事过程中的兴奋性神经元。 AIM＃4使用Leroy Hood Institute的独特专业知识来构建 基因调节网络将比较新皮质和丘脑转录组的变化 未感染的对照小鼠，RML主要是感染的小鼠，以及用双GSI + Q治疗治疗的RML感染小鼠。 我们的目标是学习随着感染而改变了哪些功能基因途径，哪些是 纠正或不通过治疗纠正。目标＃5是继续开发和使用成熟的感染大脑 领域以检验我们的假设。