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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.

总结

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

Increased Transcript Complexity in Genes Associated with Chronic Obstructive Pulmonary Disease.

与慢性阻塞性肺疾病相关的基因的转录本复杂性增加。

DOI：
10.1371/journal.pone.0140885
发表时间：
2015
期刊：
PloS one
影响因子：
3.7
作者：
Lackey L;McArthur E;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

In vivo architecture of the telomerase RNA catalytic core in Trypanosoma brucei.