Using High Throughput Approach to Identify/Characterize Functional Variants on MS
使用高通量方法在 MS 上识别/表征功能变异
基本信息
- 批准号:9670361
- 负责人:
- 金额:$ 16.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-20 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Abstract
Multiple sclerosis (MS) is an autoimmune disease for which there is limited
pathogenic understanding and no cure. Genome wide association studies
(GWAS) on MS have identified >200 MS-associated loci. These loci represent
thousands of genetic variants, usually in single nucleotide polymorphisms
(SNPs), in linkage disequilibrium (LD). However, GWAS doesn't tell which one of
them is the causal/functional SNP (fSNP) in each locus. This technical drawback
leaves a “gap” between GWAS and specific mechanism that translates into
limited opportunities for biological insight and therapeutic intervention. To
overcome this limitation, we have developed two novel techniques: functional
Single Nucleotide Polymorphism-seq (fSNP-seq) and Flanking Restriction
Enzyme-mediated DNA Pulldown (FREP). fSNP-seq is a high throughput method
to identify experimentally which SNPs are likely to bind regulatory proteins and
therefore to represent fSNPs. FREP uses an fSNP sequence as “bait” to identify
associated regulatory proteins in a semi high throughput way. Using these
techniques, we have identified three fSNPs on a MS-associated CD40 locus that
have been confirmed by EMSA, an allele-specific luciferase reporter assay and
CRISPR/Cas9, and we also identified four regulatory proteins that regulate CD40
expression via these fSNPs. On the basis of these preliminary data, we propose
two aims to apply our new methods to the entire GWAS data on MS. First, we will
use our new insights into CD40 locus to define a potentially targetable CD40
regulatory protein complex. Second, we will employ fSNP-seq to undertake high-
throughput identification of fSNPs among 4573 SNPs in LD with 196 risk loci for
MS. We will use FREP to systematically identify regulatory proteins that control
the expression of MS-associated genes via the MS fSNPs by focusing on the
MS-associated antigen presenting genes such as CD86, CD80 and MHCI for this
R21 application. Together, these studies will help us to generate a MS-
associated signal transduction and allele-specific transcription network (MS-
STAST network), with the goal of identifying novel targets for MS therapy.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gang Li其他文献
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