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Identifying Disease-Associated Mutations That Alter RNA Structure

识别改变 RNA 结构的疾病相关突变

基本信息

批准号：
7912887
负责人：
M Joan CURCIO
金额：
$ 23.79万
依托单位：
WADSWORTH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-12 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7912887
关键词：
Adopted Affect Algorithms Amino Acid Sequence Base Pairing Blood capillaries Capillary Electrophoresis Cataloging Catalogs Cellular Structures Chemicals Code Computer Analysis DNA Sequence Rearrangement Data Data Set Databases Dimensions Dimethyl Sulfoxide Disease Disease Association Etiology Functional RNA Future Gene Expression Regulation Gene Mutation Genes Genetic Genome Hamartoma Hereditary Disease Human Human Genetics Human Genome Hydroxyl Radical Induced Mutation Investigation Lead Link Location Malignant Neoplasms Maps Medicine Messenger RNA Molecular Molecular Conformation Molecular Target Multiple Hamartoma Syndrome Mutation Nucleotides PTEN gene Peptide Sequence Determination Play Predisposition Probability Process RNA RNA Conformation RNA Decay RNA analysis Rana Regulation Research Role Scanning Single Nucleotide Polymorphism Site Structure Systems Biology Technology Therapeutic Thermodynamics Transcript Translation Initiation Untranslated Regions Variant capillary effective therapy genome wide association study high throughput analysis human disease novel therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Genome wide association studies (GWAS) pinpoint the specific location in the human genome that is associated with a particular disease. Often, the regions of the genome identified in these studies are non- coding, i.e. do not change the sequence of the protein encoded by a gene. One possible mechanism by which a mutation can cause a disease without changing the protein sequence is by changing the structure of the messenger RNA (mRNA). Changes in the structure of the mRNA (in particular in the untranslated regions (UTRs)) can alter gene regulation. This is because significant components of the cell's regulatory machinery are encoded in the UTRs. This is the case for mutations in the untranslated region of the PTEN gene, which cause a rare genetic disorder called Cowden's Syndrome (which results in Hamartoma and Cancer) (Teresi et al., 2007). We hypothesize that those mutations in UTR mRNA that significantly alter its structure can modify the regulatory machinery of the gene and lead to the disease. We have developed both computational and experimental approaches to assess the structural changes caused by specific mutations in mRNA UTRs. We will scan all known disease-associated mutations in the Human Genetic Mutation database (HGMD) computationally to identify the subset that cause the largest changes in UTR mRNA structure. We will then confirm our findings using a high-throughput experimental approach we have developed that leverages multiplexed capillary electrophoresis technology (Mitra et al., 2008). This will allow us to identify and validate a subset of known disease-associated mutations where the structure of the mRNA is altered by mutation. These data will focus the research aimed at developing molecular treatments for the diseases associated with these mutations on the RNA. Our results will also begin to elucidate molecular mechanisms associated with Human disease in non-coding regions of the Human genome. We aim to identify disease-associated mutations in the human genome that alter the structure of the messenger mRNA using computational and experimental approaches. By identifying the disease-associated mutations that alter regulatory RNAs, we will identify novel molecular targets for therapeutic development.

描述(由申请人提供)：全基因组关联研究(GWAS)精确定位与特定疾病相关的人类基因组中的特定位置。通常，在这些研究中确定的基因组区域是非编码的，即不改变由基因编码的蛋白质的序列。突变可以在不改变蛋白质序列的情况下导致疾病的一种可能机制是通过改变信使RNA(信使RNA)的结构。信使核糖核酸结构的改变(尤其是非翻译区)可以改变基因调控。这是因为细胞调控机制的重要组成部分是在UTRs中编码的。PTEN基因非翻译区的突变就是这种情况，它会导致一种罕见的遗传性疾病，称为考登综合症(导致错构瘤和癌症)(Teresi等人，2007年)。我们假设，那些显著改变其结构的UTRmRNA突变可以改变该基因的调节机制，从而导致疾病。我们已经开发了计算和实验方法来评估由特定的mRNA UTRs突变引起的结构变化。我们将扫描人类基因突变数据库(HGMD)中所有已知的与疾病相关的突变，以确定导致UTRmRNA结构变化最大的子集。然后，我们将使用我们开发的利用多路毛细管电泳技术的高通量实验方法来证实我们的发现(Mitra等人，2008年)。这将使我们能够识别和验证已知的与疾病相关的突变的子集，其中mRNA的结构因突变而改变。这些数据将把研究的重点放在RNA上，旨在开发与这些突变相关的疾病的分子治疗方法。我们的结果还将开始阐明与人类基因组非编码区的人类疾病相关的分子机制。我们的目标是利用计算和实验方法识别人类基因组中与疾病相关的突变，这些突变改变了信使mRNA的结构。通过识别改变调控RNA的疾病相关突变，我们将为治疗开发确定新的分子靶点。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel application of pattern recognition for accurate SNP and indel discovery from high-throughput data: targeted resequencing of the glucocorticoid receptor co-chaperone FKBP5 in a Caucasian population.

DOI：
10.1016/j.ymgme.2011.08.019
发表时间：
2011-12
期刊：
MOLECULAR GENETICS AND METABOLISM
影响因子：
3.8
作者：
Pelleymounter, Linda L.;Moon, Irene;Johnson, Julie A.;Laederach, Alain;Halvorsen, Matt;Eckloff, Bruce;Abo, Ryan;Rossetti, Sandro
通讯作者：
Rossetti, Sandro

Rapid quantification and analysis of kinetic •OH radical footprinting data using SAFA.

DOI：
10.1016/s0076-6879(09)68003-4
发表时间：
2009
期刊：
METHODS IN ENZYMOLOGY
影响因子：
0
作者：
Simmons, Katrina;Martin, Joshua S.;Shcherbakova, Inna;Laederach, Alain
通讯作者：
Laederach, Alain

Disease-associated mutations that alter the RNA structural ensemble.

DOI：
10.1371/journal.pgen.1001074
发表时间：
2010-08-19
期刊：
PLoS genetics
影响因子：
4.5
作者：
Halvorsen M;Martin JS;Broadaway S;Laederach A
通讯作者：
Laederach A

Strategies for articulated multibody-based adaptive coarse grain simulation of RNA.

基于铰接多体的 RNA 自适应粗粒模拟策略。

DOI：
10.1016/b978-0-12-381270-4.00003-2
发表时间：
2011
期刊：
Methods in enzymology
影响因子：
0
作者：
Poursina,Mohammad;Bhalerao,KishorD;Flores,SamuelC;Anderson,KurtS;Laederach,Alain
通讯作者：
Laederach,Alain

Membrane RNAs in bacteria.

细菌中的膜 RNA。