NMR OF TRINUCLEOTIDE REPEATS--NEURODEGENERATIVE DISEASE

描述：这是一份修订后的提案。我们的长期目标是建立一个 全面的结构库，将提供以下信息 核酸三维结构的预测建模 具有生物学意义的序列。我们的目标是最终 能够将序列信息与生物功能相关联 已知的结构模块和主题。最初的焦点是三胞胎 重复(Tr)序列。分子的自发递进链长扩展 这些tr序列与10多个遗传性疾病有关。 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。这项研究强调确定 区分基因的分子特征和基本性质 不可变的tr序列是可变的，而长序列是短的。 这是关于基于结构的树关联机制的信息 序列的目的是对树之间的联系提供可能的见解 扩张性和遗传性神经退行性疾病。了解 TR序列的结构和动力学也预期为 有助于确定诊断和治疗目标 与激素受体相关的遗传病。 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”下使用核磁共振波谱。(X=A， C、G或T，n=重复次数)。核磁共振信息将是 与从紫外线测量得出的热力学参数相关联。这个 具体目标包括：1)序列比对的特征和 GAA和TTC tR序列的螺旋构象及其变异 这些性质作为链长的函数；2)高 拆分结构和性质，如构象交换和 显示不寻常的CAG、CGG、GAC和新的TR序列的灵活性 特征；3)折叠拓扑和折叠结构的刻画 更长的tr序列；4)研究 同系双链和互补异系双链。关于结构的研究 作为链长的函数的跃迁。

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.