Supplement to Existing Grant for the acquisition of a circular dichroism spectrometer at Marquette University's Chemistry Department

现有拨款的补充，用于在马凯特大学化学系购买圆二色性光谱仪

基本信息

批准号：
9895398
负责人：
Nicholas J Reiter
金额：
$ 11.3万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-15 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895398
关键词：
Address Adopted Aging Architecture Binding Binding Proteins Biochemical Biological Assay Biological Models Biology Bladder Cell Differentiation process Cell physiology Cells Chemistry Chromatin Chromosomal Stability Chromosomes Circular Dichroism Complex Cryoelectron Microscopy DNA Damage DNA Double Strand Break Degenerative Disorder Development Disease Double Strand Break Repair Electrophoretic Mobility Shift Assay Elements Enzymes Epigenetic Process Excision Future G-Quartets Gap Junctions Gene Expression Gene Expression Profile Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genome Stability Genomic approach Goals Grant Guanine Heterochromatin Histones Human Human Genome Hybrids Immunofluorescence Immunologic Immunoprecipitation In Vitro KDM1A gene Kinetics Lead Length Link Lysine Malignant Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Molecular Multienzyme Complexes Mutation Analysis Neoplasm Metastasis Neuroblastoma Nucleic Acid Binding Oncogenic Pathway interactions Play Positioning Attribute Property Prostate Proteins RNA Regulator Genes Regulatory Pathway Research Project Grants Resolution Ribonucleosides Role Signal Transduction Specificity Structure Telomere Shortening Tertiary Protein Structure Transcriptional Regulation Universities Untranslated RNA X-Ray Crystallography Yeasts analytical ultracentrifugation base chromatin remodeling crosslink demethylation epigenetic regulation functional group histone methylation human disease in vivo insight malignant breast neoplasm neuron development nucleic acid structure programs protein complex protein function recruit repair enzyme response scaffold structural biology telomere therapeutic development therapeutic target transcription factor

项目摘要

This research project is centered on the hypothesis that ribonucleic acid (RNA) structure and RNA-chromatin associated protein interactions play crucial roles in maintaining genome stability. Non-coding RNAs (ncRNAs) serve as key regulators of gene expression and are known to physically associate with chromatin-associated proteins to organize changes in gene architecture during specific development stages of the cell. A subset of these RNA-protein interactions are linked to ageing, cancer metastasis, and neuronal development. As genomic approaches begin to identify RNA-protein associations and their links to cancer, there remains limited information about epigenetic-based RNA binding proteins at the molecular level. We seek to understand how RNA functionally interacts with the lysine specific demethylase-1 (LSD1) protein enzyme. LSD1 is an essential histone methylation regulator and has oncogenic properties in several cancers including: prostate, bladder, neuroblastoma, lung, and breast cancer. LSD1 is implicated in cancer through its vast interaction network. LSD1 also interacts with many RNA molecules involved in cell differentiation and can function to regulate conserved RNA-mediated repressor complexes in the cell. An ncRNA, termed TERRA, enables LSD1 to interact with a DNA double strand break repair enzyme at the ends of chromosomes (telomeres), demonstrating that the RNA binding properties of LSD1 are important for gene regulation. TERRA is a regulatory RNA that is transcribed from yeast to humans and can adopt a non-canonical guanine quadruplex (GQ) RNA architecture in vitro and in vivo. TERRA’s abundance in the cell correlates with progressive telomere shortening and the stabilization of telomeric heterochromatin. We hypothesize that RNA-LSD1 assemblies play key roles in gene expression and propose that GQ RNAs serve as crucial regulators of chromatin-associated proteins. The proposed studies will 1) elucidate the biochemical and structural mechanisms of a TERRA RNA-LSD1 interaction and 2) examine how non-canonical structured RNAs contact LSD1 to influence telomeric regulatory pathways. The long-term goal of this project is to understand how RNA structure influences LSD1 regulatory networks. Results from these studies will provide insight into the mechanisms of RNA-based epigenetic regulation and serves as a starting point in the development of ‘tailored’ probes that target histone methylation regulators in a pathway-specific manner.

该研究项目的核心假设是核糖核酸 (RNA) 结构 RNA-染色质相关蛋白相互作用在维持非编码 RNA (ncRNA) 是基因的关键调节因子。表达并已知与染色质相关蛋白物理结合在细胞的特定发育阶段组织基因结构的变化。这些 RNA-蛋白质相互作用的子集与衰老、癌症转移和随着基因组方法开始识别 RNA 蛋白质。协会及其与癌症的联系，有关的信息仍然有限我们试图在分子水平上了解基于表观遗传学的 RNA 结合蛋白。 RNA 如何与赖氨酸特异性去甲基化酶 1 (LSD1) 蛋白发生功能性相互作用 LSD1 是一种重要的组蛋白甲基化调节因子，具有致癌性。多种癌症的特性，包括：前列腺癌、膀胱癌、神经母细胞瘤、肺癌和 LSD1 通过其庞大的相互作用网络与癌症有关。还与许多参与细胞分化的 RNA 分子相互作用并发挥作用调节细胞中保守的 RNA 介导的阻遏复合物，称为 TERRA，使 LSD1 能够与 DNA 双链断裂修复相互作用染色体末端（端粒）的酶，证明 RNA 结合 LSD1 的特性对于基因调控很重要。 TERRA 是一种调节性 RNA。从酵母转录到人类并可以采用非规范的鸟嘌呤四链体 (GQ) TERRA 在细胞中的丰度与体外和体内的 RNA 结构相关。端粒逐渐缩短和端粒异染色质稳定。我们认为 RNA-LSD1 组装体在基因表达和提出 GQ RNA 作为染色质相关蛋白的重要调节因子。拟议的研究将1）阐明生物化学和结构机制 TERRA RNA-LSD1 相互作用和 2) 检查非规范结构的 RNA 联系LSD1来影响端粒调控途径是这个的长期目标。该项目旨在了解 RNA 结构如何影响 LSD1 调控网络。这些研究的结果将深入了解基于 RNA 的机制表观遗传调控并作为“定制”发展的起点以通路特异性方式靶向组蛋白甲基化调节因子的探针。