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K 02 AG 034176独立科学家职业发展奖的行政补充申请，该奖项受到超级风暴桑迪的影响。该奖项的研究计划致力于开发类肽化合物，阻断ApoE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）治疗药物。职业发展计划概述了蛋白质化学，类肽化合物合成，药物设计和开发，体内微透析，获得进行AD临床试验的经验，以及指导初级教师和博士生的培训。由于纽约大学医学院校园持续的洪水，我们的多个研究设施被暂时关闭，有些仍然没有重新开放，这影响了校园的学术和培训活动。暂时关闭包括我们的实验室和动物群设施，这些设施被洪水淹没，在五周内无法进入;因此，所有为计划的实验和正在进行的实验而繁殖AD转基因（Tg）小鼠的努力都被暂停。尽管遇到挫折，该奖项的具体目标仍然没有改变。目的I概述了apoE/A β结合的类肽拮抗剂的开发，其是基于A β 12 - 28 P的结构设计的，A β 12 - 28 P是一种在我们的初步研究中使用的合成肽，以证明apoE/A β相互作用的药理学阻断防止AD Tg小鼠中的记忆障碍并减少A β斑块负荷（Sadowski等，PNAS 2006; 103：18787）。目的II概述了A β 12 - 28 P及其最佳类肽衍生物在表达各种人apoE亚型的AD Tg小鼠中的治疗，正如在表达鼠apoE的小鼠中进行的初步研究一样。目的III研究阻断apoE/ApoE相互作用是否阻止ApoE在神经元内的蓄积并改善脑ApoE清除。本补充报告的研究计划是建立在为实现最初的具体目标而取得的成果基础上的，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，我们有一个独特的具有拟肽修饰的环状A β 12 - 28 P衍生物文库，我们打算对其进行测试。为了实现目标II，我们开发并表征了一种新型AD Tg模型小鼠APPSW/PS1dE9 apoE-TR与人apoE亚型E2、E3和E4的小鼠apoE基因的靶向置换（TR）。在APPSW/PS1dE9/apoE2-TR和APPSW/PS1dE9/apoE4-TR小鼠中，A β 12 - 28 P处理均减少脑中A β的积累。在本补充中，我们计划表征APPSW/PS1dE9/apoE3-TR系中的A β 12 - 28 P处理以及用最有希望的类肽化合物处理所有三个TR系的效果。对于目标III，我们已经开发了一个神经元-星形胶质细胞共培养系统，以研究apoE/AAPO2在体外的相互作用，我们计划研究各种人类apoE亚型对神经元内AAPO2病理的影响。此外，这项行政补充将有助于恢复我原来的职业发展计划，该计划在超级风暴之后由于我们校园的多个设施关闭而中断，并且需要将个人努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。