Investigating molecular mechanisms of cross-species prion transmission

研究跨物种朊病毒传播的分子机制

• 批准号: 9066229
• 负责人: Timothy Daniel Kurt
• 金额: $ 4.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-19 至 2016-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9066229
• 关键词: Adhesives; Alzheimer' s Disease; Amino Acid Sequence; Amino Acids; Amyloid; Amyloid Fibrils; Animal Feed; Arginine; Biological Assay; Biomedical Research; Bovine Spongiform Encephalopathy; Cattle; Cessation of life; Chronic Wasting Disease; Creutzfeldt-Jakob Syndrome; Crystallography; Deer; Disease; Doctor of Philosophy; Goals; Gray unit of radiation dose; Health; Human; In Vitro; Infection; Institution; Investigation; Left; Length; Mentored Research Scientist Development Award; Mentors; Molecular; Mus; Nature; Neurodegenerative Disorders; North America; Parkinson Disease; Pathogenesis; Pathologist; Peptides; Polymers; Positioning Attribute; PrP; PrPSc Proteins; Predisposition; Prevention; Principal Investigator; Prion Diseases; Prions; Protein Isoforms; Proteins; Province; Publishing; Research; Resistance; Role; Scientist; Sheep; Side; Structural Biologist; Structure; Study models; Testing; Time; Transgenic Mice; Variant; Wild Type Mouse; Work; alpha helix; amyloid formation; base; career; conformer; design; disease transmission; experience; human disease; in vivo; innovation; insight; interest; mouse model; mutant; novel; novel strategies; prion-based; protein misfolding; research study; synuclein; tau Proteins; therapy development; transmission process

 DESCRIPTION (provided by applicant): Chronic wasting disease (CWD) is a prion disorder of elk and deer that is uniformly fatal, exceedingly difficult to control in nature, and has been detected in over 20 states and 2 Canadian provinces. Given that humans, food animals, and wildlife are increasingly exposed to CWD prions, the potential for cross-species CWD transmission is a major concern. Prion transmission occurs when the normal cellular prion protein, PrPC, is converted to a misfolded and infectious isoform called PrPSc. Sequence similarity between host PrPC and infectious PrPSc is a key factor in determining prion susceptibility, however the specific amino acids that control susceptibility to CWD are not clear. Recent studies suggest that a 10-residue loop connecting a β -strand with an α -helix (β2-α2 loop) impacts the ease of cross-species prion transmission. Furthermore, crystallography experiments have shown that β2-α2 loop peptide segments can interact by tightly interlacing their amino acid side chains to form a steric zipper, a structure that may promote protein-misfolding. The central hypothesis of this proposal is that amino acids within the β2-α2 loop of PrPC support prion conversion and impact cross-species prion transmission. The objectives of these studies are: (1) to solve the structural mechanism underlying human susceptibility or resistance to CWD and other prions, and (2) to define the role of steric zippers in promoting PrPC to PrPSc conversion among different prion conformational variants, known as strains. To accomplish these objectives, this work will use novel transgenic mouse models expressing chimeric forms of human PrPC as well as a highly innovative in vitro prion conversion assay. Dr. Timothy Kurt is a DVM, PhD with nine years of experience studying prion diseases, including CWD. His research interests include the pathogenesis and prevention of protein- misfolding disorders such as prion, Alzheimer's and Parkinson's diseases. Dr. Kurt's primary career goal is to become a principal investigator at an academic biomedical research institution, and the K01 award would support his progress to independence by providing protected time to pursue research with highly supportive mentors. He has assembled an outstanding mentoring and advising team that includes veterinary scientists, pathologists, a structural biologist and a chemist with expertise in amyloid formation. Five years of support is requested.

 描述（由适用提供）：慢性浪费疾病（CWD）是一种麋鹿和鹿的疾病，是致命的，在自然界中很难控制，并且已经在20多个州和2个加拿大计划中被发现。鉴于人类，食用动物和野生动植物越来越暴露于CWD Prions，因此CWD传播的潜力是主要问题。当正常细胞蛋白PRPC转化为称为PRPSC的错误折叠和传染性同工型时，就会发生prion传播。宿主PRPC和感染性PRPSC之间的序列相似性是确定prion敏感性的关键因素，但是控制CWD敏感的特定氨基酸尚不清楚。最近的研究表明，将β-链与α-螺旋（β2-α2回路）连接的10个残留回路会影响跨物种prion传播的易感性。此外，晶体学实验表明，β2-α2环肽段可以通过紧密交织其氨基酸侧链形成空间拉链来相互作用，这种结构可能促进蛋白质不满意。该提案的中心假设是PRPC的β2-α2环内的氨基酸支持prion conversion依和撞击跨物种的prion传播。这些研究的目的是：（1）解决人类易感性或对CWD和其他prions的抗性的结构机制，以及（2）定义空间拉链在将PRPC推广到PRPC转化为PRPSC转换不同的prion构象变体之间的作用，称为菌株。为了实现这些目标，这项工作将使用表达人PRPC的嵌合形式的新型转基因小鼠模型以及高度创新的体外prion conversion依分析。蒂莫西·库尔特（Timothy Kurt）博士是DVM博士学位，拥有9年的研究疾病的经验，包括CWD。他的研究兴趣包括对蛋白质错误折叠疾病的发病机理和预防，例如prion，阿尔茨海默氏症和帕金森氏病。库尔特博士的主要职业目标是成为一家学术生物医学研究机构的首席研究员，而K01奖将通过提供受保护的时间来与高度支持的导师进行研究，以支持他对独立的进步。他组建了一个杰出的心理和咨询团队，其中包括兽医科学家，病理学家，结构性生物学家以及具有淀粉样蛋白形成专业知识的化学家。要求提供五年的支持。