Degenerative and Dementing Diseases of Aging

DESCRIPTION（由申请人提供）：总体在4个科学项目和4个核心中，我们提出研究asβ PrP和tau朊病毒引起的神经变性。朊病毒导致阿尔茨海默病和其他神经退行性疾病（包括额颞叶痴呆、帕金森病和ALS）的发现，为破译这些疾病的发病机制和开发新的治疗方法开辟了新的研究策略。理解所有朊病毒的基础是定义一种特定蛋白质在成为朊病毒时所经历的结构转变。在这个P01更新申请中，我们计划利用我们和其他人发表的新数据，这些数据认为，像PrP一样，asas和tau可以获得自传播的构象；因此，它们是朊病毒。在每种情况下，这些可选择的构象都富含ß-sheet结构，并且很容易在淀粉样蛋白原纤维中聚合，而淀粉样蛋白原纤维通常凝结成斑块或缠结。在Project 1中，我们拟利用我们所建立的基因型小鼠来研究阿斯朊病毒菌株的特性，建立能够检测阿斯朊病毒和tau朊病毒的培养细胞生物检测方法，利用表达bank vole (BV) PrP或嵌合Hu/BVPrP转基因的基因型小鼠来研究人类（Hu） PrP朊病毒，并确定表达BVPrP的培养细胞是否能够支持人类朊病毒株的复制。在Project 2中，我们建议继续对重组PrP形成的PrPSc进行结构研究，利用89-mer片段启动无锚定PrPSc朊病毒的复制，继续对PrPSc进行结构研究

DESCRIPTION (provided by applicant): Overall In four scientific projects and four cores, we propose to study Aß PrP, and tau prions causing neurodegeneration. The discovery that prions cause Alzheimer's disease and other neurodegenerative diseases including frontotemporal dementias, Parkinson's disease, and ALS opens new research strategies for deciphering the pathogenesis of these illnesses and developing novel therapeutic approaches. Fundamental to understanding all prions is defining the structural transition that a particular protein undergoes when it becomes a prion. In this P01 renewal application, we plan to exploit new data published by us and others contending that Aß and tau, like PrP, can acquire conformations that are self-propagating; thus, they are prions. In each case, these alternative conformations are enriched for ß-sheet structure and readily polymerize in amyloid fibrils that often condense into plaques r tangles. In Project 1, we propose to study the properties of strains of Aß prions using bigenic mice that we created, to develop cultured cell bioassays that can detect Aß and tau prions, to investigate human (Hu) PrP prions using bigenic mice expressing bank vole (BV) PrP or chimeric Hu/BVPrP transgenes, and to determine if cultured cells expressing BVPrP can support the replication of human prion strains. In Project 2, we propose to continue structural studies of PrPSc formed from recombinant PrP utilizing an 89-mer fragment that initiated replication of anchorless PrPSc prions, to continue structural studies of Aß with emphasis on naturally occurring mutants, and to initiate structural studies of tau prions. In Project 3, we propose to determine the structure of Aß prions by solution and solid-state NMR; to monitor Aß assembly using multiple probes that are sensitive to both global and local conformations; to create thioamide- containing peptides and foldamers that enhance or inhibit individual steps of amyloid initiation, elongation, and fragmentation; and to synthesize a series of crosslinking reagents to probe the distribution of distances between Lys and Arg residues in Aß, PrP and tau prions. In Project 4, we propose to adapt and apply integrative structural modeling to protein self-assembly, thus facilitating simultaneous modeling of multiple structural states based on sparse, noisy, ambiguous and incoherent data of different kinds.