Peptoid Antagonists of the ApoE/ABeta Interaction as a Novel Anti-ABeta Therapy.

ApoE/Aβ 相互作用的类肽拮抗剂作为一种新型抗 Aβ 疗法。

• 批准号: 8742110
• 负责人: MARTIN Joseph SADOWSKI
• 金额: $ 10.8万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-20 至 2015-12-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742110
• 关键词: Abbreviations; Academic Training; Administrative Supplement; Adverse effects; Affect; Agonist; Alleles; Alzheimer' s Disease; Amides; Amino Acid Substitution; Amino Acids; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Applications Grants; Asses; Award; Binding; Binding Sites; Biological; Biological Availability; Biomedical Technology; Blood - brain barrier anatomy; Blood Vessels; Brain; Breeding; Chemistry; Chimera organism; Chronic; Clinical Trials; Coculture Techniques; Collaborations; Data; Deposition; Deuterium; Development; Development Plans; Doctor of Philosophy; Drug Design; Drug Kinetics; Equilibrium; Faculty; Floods; Genes; Half-Life; Human; Hydrogen; In Vitro; Intercellular Fluid; Investigation; K-Series Research Career Programs; Knock-out; Laboratories; Lead; Libraries; Ligands; Mass Spectrum Analysis; Measurement; Mediating; Memory impairment; Mentors; Metabolism; Microdialysis; Modification; Mus; N-substituted Glycines; Neurons; Pathology; Peptides; Peptoids; Permeability; Pharmacodynamics; Population; Protein Chemistry; Protein Isoforms; Proteins; Research; Resistance; Scientist; Serum; Site; Structure; Students; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Training; Training Activity; Transgenic Mice; Wild Type Mouse; Work; animal colony; apolipoprotein E-3; apolipoprotein E-4; base; behavior test; career development; design; drug development; experience; improved; in vivo; inhibitor/antagonist; medical schools; novel; novel therapeutic intervention; peptidomimetics; prevent; research facility; research study; response; restoration; reuptake; synthetic peptide; transgenic model of alzheimer disease; treatment effect

Project summary: This is an application for an administrative supplement to K02 AG034176 Independent Scientist Career Development Award, which was affected by the super storm Sandy. The research plan of this award pursues development of peptoid compounds blocking the interaction between Aß and apolipoprotein (apo) E as novel Alzheimer’s disease (AD) therapeutics. The career development plan outlines training in protein chemistry, synthesis of peptoid compounds, drug design and development, in vivo Aß microdialysis, gaining experience in conducting AD clinical trials, and mentoring junior faculty and PhD students. Due to flooding sustained by the NYU School Medicine campus multiple of our research facilities were temporarily closed and some still have not reopened, which compromised on campus academic and training activities. Temporary closure included our laboratory and our animal colony facility, which was flooded and became inaccessible for five weeks; therefore all efforts to breed AD transgenic (Tg) mice for planned experiments and ongoing experiments on these mice were suspended. Despite setbacks, the specific aims of the award remained unchanged. Aim I outlines development of peptoid antagonists of the apoE/Aß binding, which are designed based on the structure of Aß12- 28P, a synthetic peptide used in our preliminary study to demonstrate that pharmacological blocking of the apoE/Aß interaction prevents memory impairment and reduces Aßplaque load in AD Tg mice (Sadowski et al. PNAS 2006;103:18787). Aim II outlines treatment with Aß12-28P and its most optimal peptoid derivatives in AD Tg mice expressing various human apoE isoforms, as the preliminary study was done in mice expressing murine apoE. Aim III investigates whether blocking the apoE/Aß interaction prevents intraneuronal accumulation of Aß and improves brain Aß clearance. The research plan of this supplement builds on results, which were obtained working toward the original specific aims and proposes studies to restore losses caused by the super storm Sandy. For aim I we have a unique library of cyclic Aß12-28P derivatives with peptoid modifications which we propose to test. For aim II we have developed and characterized a novel AD Tg model mice APPSW/PS1dE9 apoE-TR with targeted replacement (TR) of the mouse apoE gene for human apoE isoforms E2, E3, and E4. Aß12-28P treatment in both APPSW/PS1dE9/apoE2-TR and APPSW/PS1dE9/apoE4-TR mice reduced brain Aß accumulation. In this supplement we plan to characterize Aß12-28P treatment in APPSW/PS1dE9/apoE3-TR line and effects of the treatment with the most promising peptoid compound in all three TR lines. For aim III we have developed a neuronal-astrocytic co-culture system to study the apoE/Aß interaction in vitro and we plan to investigate the effect of various human apoE isoforms on intraneuronal Aß pathology. Furthermore, this administrative supplement would aid to restore my original career development plan, which was disrupted in the aftermath of the super storm due to closure of multiple facilities in our campus and a need to divert personal effort from career development and training activities toward restoration of research capacity of our laboratory.

项目概要： 这是对受到超级风暴桑迪影响的K02 AG034176独立科学家职业发展奖的行政补充申请。该奖项的研究计划致力于开发类肽化合物，阻断 Aß 和载脂蛋白 (apo) E 之间的相互作用，作为新型阿尔茨海默病 (AD) 疗法。职业发展计划概述了蛋白质化学、类肽化合物的合成、药物设计和开发、体内Aß微透析、获得进行AD临床试验的经验以及指导初级教师和博士生等方面的培训。由于纽约大学医学院校园遭受洪水侵袭，我们的多个研究设施暂时关闭，有些尚未重新开放，这影响了校园的学术和培训活动。临时关闭包括我们的实验室和动物群体设施，这些设施被洪水淹没，五周内无法进入；因此，所有为计划中的实验和正在进行的实验而培育 AD 转基因 (Tg) 小鼠的努力都被暂停了。尽管遇到了挫折，该奖项的具体目标仍然没有改变。目标 I 概述了 apoE/Aß 结合的类肽拮抗剂的开发，该拮抗剂是根据 Aß12-28P 的结构设计的，Aß12-28P 是我们初步研究中使用的一种合成肽，旨在证明药物阻断 apoE/Aß 相互作用可以防止 AD Tg 小鼠的记忆障碍并减少 Aßplaque 负荷（Sadowski 等人。 PNAS 2006;103:18787）。 Aim II 概述了在表达各种人类 apoE 亚型的 AD Tg 小鼠中使用 Aß12-28P 及其最优化的类肽衍生物进行治疗，因为初步研究是在表达鼠类 apoE 的小鼠中进行的。目标 III 研究阻断 apoE/Aß 相互作用是否可以防止 Aß 的神经元内积累并改善大脑 Aß 清除率。本增刊的研究计划建立在为实现最初的具体目标而取得的成果的基础上，并提出了恢复超级风暴桑迪造成的损失的研究。对于目标 I，我们拥有一个独特的带有类肽修饰的环状 Aß12-28P 衍生物库，我们建议对其进行测试。对于目标 II，我们开发并表征了一种新型 AD Tg 模型小鼠 APPSW/PS1dE9 apoE-TR 将小鼠 apoE 基因定向替换 (TR) 为人 apoE 同工型 E2、E3 和 E4。 APPSW/PS1dE9/apoE2-TR 和 APPSW/PS1dE9/apoE4-TR 小鼠中的 Aß12-28P 治疗减少了脑内 Aß 的积累。在本补充材料中，我们计划描述 APPSW/PS1dE9/apoE3-TR 系中的 Aß12-28P 治疗以及所有三个 TR 系中最有希望的类肽化合物治疗的效果。对于目标 III，我们开发了一种神经元-星形细胞共培养系统来研究体外 apoE/Aß 相互作用，并且我们计划研究各种人类 apoE 异构体对神经元内 Aß 病理学的影响。此外，这项行政补充将有助于恢复我原来的职业发展计划，该计划在超级风暴过后被打乱，原因是我们校园的多个设施关闭，并且需要将个人精力从职业发展和培训活动转移到恢复我们实验室的研究能力。