NMR OF TRINUCLEOTIDE REPEATS--NEURODEGENERATIVE DISEASE

说明：这是一份修订后的提案。 长期目标是建立一个 一个全面的结构库，将为 核酸三维结构的预测建模 具有生物学意义的序列。 目标是最终 能够根据以下信息将序列信息和生物功能关联起来 已知的结构模块和基序。 最初的重点是三重态 重复（TR）序列。 自发渐进链长扩张 这些TR序列与10多种遗传性 神经退行性疾病，包括脆性X综合征、肌强直 营养不良和肯尼迪病 该研究强调识别 分子特征和基本性质，区分遗传 从非可变TR序列可变，从长序列短。 这一信息的结构为基础的机制，为协会的TR 序列的目的是提供可能的见解之间的联系TR 扩张和遗传性神经变性疾病。 了解 TR序列的结构和动力学也预计， 有助于确定诊断和治疗目标， TR相关的遗传疾病。 d（CXG）n序列的结构、稳定性和构象柔性 以及新发现的d（GAA）n和d（TTC）n序列 在“接近生理条件”下使用核磁共振光谱。“（X = A， C、G或T，并且n =重复的数目）。 NMR信息将是 与来自UV测量的热力学参数相关。 的 具体目的包括：1）序列比对的表征， GAA和TTC TR序列的螺旋构象以及 这些性质作为链长的函数; 2）阐明了高分子量聚乙烯的分子量分布。 解析结构和性质，如构象交换和 灵活性，CAG，CGG，GAC和新的TR序列，表现出不寻常的 特征; 3）折叠拓扑和折叠结构的刻画 长TR序列; 4）研究 同源双链体和互补异源双链体。 结构研究 作为链长的函数的转变。

DESCRIPTION: This is a revised proposal. The long term goal is to build a comprehensive structural library that will provide information for predictive modeling of three-dimensional structures of nucleic acid sequences of biological significance. The objective is to eventually be able to correlate sequence information and biological function based on known structural modules and motifs. The initial focus is on the triplet repeat (TR) sequences. Spontaneous progressive chain length expansion of these TR sequences has been implicated in more than 10 hereditary neurodegenerative diseases, including fragile X-syndrome, myotonic dystrophy, and Kennedy's disease. The research emphasizes identifying the molecular features and basic properties that differentiate the genetically mutable from non-mutable TR sequences, and the short from long sequences. This information on the structure-based mechanisms for association of TR sequences is aimed at giving possible insights into the link between TR expansion and an hereditary neurodegenderative diseases. Understanding the structure and dynamics of the TR sequences are also anticipated to contribute to the identification of diagnostic and therapeutic targets for TR related genetic diseases. Structure, stability and conformational flexibility of d(CXG)n sequences, as well as the newly discovered d(GAA)n and d(TTC)n sequences, will be studied using NMR spectroscopy under "close to physiological conditions." (X = A, C, G or T, and n = number of repeats). The NMR information will be correlated with thermodynamics parameters derived from UV measurements. The specific aims include: 1) Characterization of the sequence alignment and helical conformation of the GAA and TTC TR sequences and the variations of these properties as a function of chain length; 2) Elucidation of the high resolution structures and properties, such as conformation exchange and flexibility, of CAG, CGG, GAC, and new TR sequences that exhibit unusual features; 3) Characterizations of folding topology and folded structures of longer TR sequences; 4) Investigation of the relative stabilities of the homo-duplexes and complementary hetero-duplexes. Studies of structural transitions as a function of chain length.