Oxytocin Modulation of Social Behavior

催产素对社会行为的调节

• 批准号: 10044651
• 负责人: Ismail A. Ahmed
• 金额: $ 6.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-02 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044651
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Amino Acids; Animal Model; Anus; Arts; Atomic Force Microscopy; Award; Biochemistry; Biological; Biology; Biophysics; Brain; Cell Nucleus; Cessation of life; Chemical Structure; Chemistry; Collaborations; Disease; Doctor of Philosophy; Dyes; Elderly; Engineering; Environment; Event; Exhibits; Fluorescence; Foundations; Frontotemporal Dementia; Funding; Genetic; Goals; Hydration status; In Vitro; Kinetics; Knowledge; Label; Leadership; Learning; Length; Light; Maps; Measurement; Measures; Mentorship; Methods; Microscopy; Mind; Mission; Molecular; Molecular Conformation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Oxytocin; Pathogenicity; Pathology; Pathway interactions; Penetration; Peptides; Phase; Phenylalanine; Population; Positioning Attribute; Process; Property; Proteins; Protons; Research; Scientist; Seeds; Site; Social Behavior; Spectrum Analysis; Structure; Technology; Tertiary Protein Structure; Testing; Time; Training; Tryptophan; Variant; Virginia; Work; aggregation pathway; base; career; chromophore; design; disorder control; doctoral student; fluorophore; graduate student; human model; in vivo; innovation; interdisciplinary approach; interest; misfolded protein; novel; novel therapeutics; prevent; prospective; protein aggregation; protein folding; protein misfolding; single molecule; structural biology; tau Proteins; tau aggregation; tau function; tool; unnatural amino acids

Project Summary/Abstract: The Goal of this proposal is to dissect the mechanistic details surrounding the nucleation and early events of tau aggregation. Tau is a key misfolding and aggregating protein associated with both Alzheimer’s disease (AD) and frontotemporal dementia (FTD). There has been a significant increase in the number of people suffering from neurodegenerative diseases, including AD and FTD and is expected to continue to rise as there are currently no cures. While many studies have attributed the aggregation of tau as a cause of the disease, the process of nucleation and self-prorogation of tau aggregation is not well understood. One major challenge has been to determine the conformational basis of tau misfolding and aggregation due to the large size of the protein. To address this challenge, minimal sequence of 31 residues has been defined as the conformational nucleus responsible for the self-propagation of tau aggregation, thus providing a foundation for investigating the early stage of nucleation. With this observation we hypothesize that residues within this minimal sequence interact with other domains of the protein to induce aggregation at the single molecule level as well as interact with other misfolded tau molecules to seed aggregation. To test this, we propose to map these interactions in a site specific manner using minimally perturbing fluorescent unnatural amino acids to shed light on the early non-fibrillar oligomer formation and the local conformational dynamics over the course of aggregation. Innovation: In order to dissect site-specific interactions, kinetics and conformational dynamics surrounding the nucleation and early aggregation events of tau, new tools are needed. Unnatural amino acids sensitive to hydration are uniquely useful to probe aggregation because of the change in local hydration exhibited when once soluble protein becomes insoluble during aggregation. Unfortunately, current technologies such as fluorescent proteins and dyes are not ideal to study intramolecular events due to their prohibitive size. Unnatural amino acids chromophores offer the desired spectroscopic qualities in a framework that is non-perturbing to both structure and function of tau, making it ideal to study the intra- and intermolecular conformational dynamics, kinetics and interactions during tau aggregation. Together this will inform our direct knowledge to help elucidate the aggregation pathway.

项目摘要/摘要： 这项提议的目标是剖析围绕成核和早期事件的机制细节。 Tau聚集态。Tau是一种关键的错误折叠和聚集蛋白，与阿尔茨海默病 (AD)和额颞叶痴呆(FTD)。人数有了显著的增长。 患有神经退行性疾病，包括AD和FTD，预计将继续上升 目前还没有治愈方法。虽然许多研究将tau的聚集归因于疾病的原因，但 Tau聚集体的成核和自比例过程还不是很清楚。一个主要的挑战是 一直在确定tau错误折叠和聚集的构象基础，这是由于tau的大小 蛋白。为了解决这一挑战，31个残基的最小序列被定义为构象 负责tau聚集的自繁殖，从而为研究tau聚集提供了基础 成核早期。根据这一观察结果，我们假设这个最小序列中的残基 与蛋白质的其他结构域相互作用，在单分子水平上诱导聚集，以及相互作用 与其他错误折叠的tau分子进行种子聚集。为了测试这一点，我们建议将这些交互映射到 位点特异性方式使用最小扰动的荧光非天然氨基酸来阐明早期 非纤维齐聚物的形成和聚集过程中的局部构象动力学。 创新：为了剖析特定部位的相互作用，动力学和构象动力学围绕着 对于tau的成核和早期聚集事件，需要新的工具。对非天然氨基酸敏感 水合作用对于探测聚集是唯一有用的，因为在以下情况下局部水合作用的变化 一旦可溶性蛋白质在聚集过程中变得不能溶解。不幸的是，目前的技术，如 由于荧光蛋白和染料的大小令人望而却步，它们不是研究分子内事件的理想材料。不自然 氨基酸生色团在不干扰的框架内提供所需的光谱性质 Tau既有结构又有功能，是研究分子内和分子间构象的理想材料 Tau聚集过程中的动力学、动力学和相互作用。总而言之，这将使我们直接了解到 有助于阐明聚集途径。