Structural and functional consequences of disease SNP's on the transcriptome

疾病 SNP 对转录组的结构和功能影响

基本信息

批准号：
10017258
负责人：
Alain T Laederach
金额：
$ 32.24万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017258
关键词：
Affect Algorithms Alleles Amyotrophic Lateral Sclerosis Award Biological Assay Cell Line Cells Chemical Structure Code Colorectal Cancer Complex Computational algorithm Computing Methodologies Congenital Megacolon DNA Data Data Analyses Databases Disease Elements Environment Etiology Funding Gene Mutation Genes Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genome Genotype Goals High Density Lipoprotein Cholesterol Human Human Genetics In Vitro Knowledge Lipase Luciferases Maps Measures Mediating Messenger RNA Modeling Molecular Molecular Conformation Mutagenesis Mutation Noise Open Reading Frames Parents Pathologic Phenotype Post-Transcriptional Regulation Proteins RNA Regulation Reporter Research Proposals Resolution Robotics Role Sampling Schizophrenia Seckel syndrome Shapes Signal Transduction Single Nucleotide Polymorphism Single Nucleotide Polymorphism Map Sorting - Cell Movement Speed Structure System Techniques Technology Testing Tetanus Helper Peptide Translations Untranslated RNA Untranslated Regions Variant Work base disease phenotype experimental study gene synthesis genetic association genetic information genome-wide human disease in vivo innovation lymphoblast mRNA Stability malignant breast neoplasm next generation sequencing novel personalized medicine protein expression therapeutic target transcriptome

项目摘要

SUMMARY Genetic association studies identify the genotypes that correlate with specific phenotypes. A significant portion of the Single Nucleotide Polymorphisms (SNPs) that associate with human disease phenotypes map outside of the protein coding regions of genes. In these cases, the precise molecular mechanism of the disease etiology is not immediately apparent. This proposal focuses specifically on SNPs that map to non-coding and UnTranslated Regions (UTRs) of genes. If these SNPs alter the structure of the RNA, they are classified as a riboSNitch. We will experimentally validate eight novel, computationally predicted riboSNitches associated with the human diseases amyotrophic lateral sclerosis, breast and colorectal cancer, dyskeratosis, Hirschsprung's disease, lipase deficiency, microcephalic dwarfism, and schizophrenia. Our work will leverage significant advances in the throughput and accuracy of chemical structure probing techniques in combination with next generation sequencing. Furthermore, these techniques now enable us to probe RNA structure in vivo allowing us to further understand how the cellular environment affects RNA folding and the function of riboSNitches. We will also perform quantitative luciferase reporter assays and leverage Tet-off inducible systems to study the functional consequences of validated riboSNitches on translation and RNA stability to establish disease causality. Together, our findings will establish SNP-induced RNA structure change in multiple new human diseases and broaden understanding of RNA structure in shaping human phenotype.

概括遗传关联研究确定与特定表型相关的基因型。很大一部分与人类疾病表型相关的单核苷酸多态性（SNP）图谱之外基因的蛋白质编码区。在这些情况下，疾病病因学的精确分子机制不是立即显而易见的。该提案特别关注映射到非编码和非编码的 SNP 基因的非翻译区 (UTR)。如果这些 SNP 改变了 RNA 的结构，则它们被归类为核糖核酸酶。我们将通过实验验证八个新颖的、计算预测的 riboSNitches 与人类疾病肌萎缩侧索硬化症、乳腺癌和结直肠癌、角化不良、先天性巨结肠疾病、脂肪酶缺乏症、小头侏儒症和精神分裂症。我们的工作将利用重要的化学结构探测技术的吞吐量和准确性的进步与下一步相结合世代测序。此外，这些技术现在使我们能够探测体内 RNA 结构，从而允许我们进一步了解细胞环境如何影响 RNA 折叠和 riboSNitches 的功能。我们还将进行定量荧光素酶报告基因检测并利用 Tet-off 诱导系统来研究经验证的 riboSNitches 对翻译和 RNA 稳定性的功能影响以确定疾病因果关系。总之，我们的研究结果将在多个新人类中建立 SNP 诱导的 RNA 结构变化。疾病并拓宽对塑造人类表型的 RNA 结构的理解。

项目成果

期刊论文数量（35）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multiple conformations are a conserved and regulatory feature of the RB1 5' UTR.

DOI：
10.1261/rna.049221.114
发表时间：
2015-07
期刊：
RNA (New York, N.Y.)
影响因子：
0
作者：
Kutchko KM;Sanders W;Ziehr B;Phillips G;Solem A;Halvorsen M;Weeks KM;Moorman N;Laederach A
通讯作者：
Laederach A

Cigarette smoking-associated isoform switching and 3' UTR lengthening via alternative polyadenylation.

DOI：
10.1016/j.ygeno.2021.11.004
发表时间：
2021-11
期刊：
Genomics
影响因子：
4.4
作者：
Xu Z;Platig J;Lee S;Boueiz A;Chase R;Jain D;Gregory A;Suryadevara R;Berman S;Bowler R;Hersh CP;Laederach A;Castaldi PJ;COPDGene Investigators
通讯作者：
COPDGene Investigators

Structure-Function Model for Kissing Loop Interactions That Initiate Dimerization of Ty1 RNA.