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High Throughput Method to Assess SNP Functionality in Prostate Cancer

高通量方法评估前列腺癌中的 SNP 功能

基本信息

批准号：
8336846
负责人：
Mary Szatkowski Ozers
金额：
$ 14.47万
依托单位：
PROTEOVISTA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8336846
关键词：
8q24 Adverse effects Affect Affinity Binding Binding Proteins Binding Sites Biological Assay Cancer Etiology Cells Clinic Colorectal Cancer Custom DNA DNA Binding DNA Microarray Chip DNA Sequence Data Devices Diagnosis Diagnostic Neoplasm Staging Disease Disease model Drug Delivery Systems Fluorescence Gene Expression Regulation Genes Genetic Genetic Variation Genome Genomics Goals Hand Human Genome Incidence Incubated Industry Junk DNA Laboratories Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Marketing Measures Medical Medicine Methods Pathway interactions Patients Phase Positioning Attribute Prevalence Protein Microchips Proteins Risk Risk Assessment S-nitro-N-acetylpenicillamine Services Single Nucleotide Polymorphism Site Sorting - Cell Movement Source Specificity TCF Transcription Factor Technology Therapeutic Translating United States Variant cancer cell cancer diagnosis cancer type chromatin immunoprecipitation commercialization cost design disorder risk ds-DNA improved malignant breast neoplasm men patient population preference prototype research study therapeutic target transcription factor tumor molecular fingerprint

项目摘要

Project Summary High Throughput Method to Assess SNP Functionality in Prostate Cancer PIs: Christopher L. Warren and Mary S. Ozers A critical unmet need in implementing personalized medicine is the ability to sort through the millions of single nucleotide polymorphisms (SNPs) present in the human genome and to pinpoint which of these DNA variations are causative in disease. A key under-studied function of SNPs is their ability to generate or disrupt genomic binding sites for transcription factors involved in cancer. Toward this goal, we are inventing the SNP-SNAP (Specificity and Affinity for Proteins) microarray as a prototype high throughput device to evaluate SNP function. The SNP-SNAP arrays will be used to display a quarter-million prostate cancer- related SNPs as double-stranded DNA molecules and to assay transcription factors (i.e. drug targets) for their binding to these SNP DNA sequences. The resulting data will be correlated with prostate cancer incidence. The million-plus data points from the SNP-SNAP arrays will be analyzed using SNP-Sequence Specificity Landscapes, creating a prostate cancer "molecular signature" that relates transcription factor binding, SNP preferences, and chromosomal position of the nearest genes. Our findings will also relate prostate cancer-associated SNP function with cancer stage and aggressiveness. Understanding SNP function will have a major impact on personalized medicine, by providing individualized disease risk assessment, identifying new personalized therapeutic targets, and predicting efficacy and potential off- target side effects of common therapeutics. The goals of this Phase I project are to: 1. Design and synthesize a customized SNP-SNAP DNA microarray to tile across a quarter-million SNPs that are associated with prostate cancer. 2. Examine the DNA binding specificity and affinity of 5 prostate cancer-related transcription factors, as purified proteins and from cell lysates, on the SNP-SNAP array and annotate the human genome with the transcription factor binding differences due to SNPs. Verify results with chromatin immunoprecipitation in prostate cancer cells. 3. Obtain SNP data from patients with prostate cancer and determine if there is a statistically significant association of functional SNPs, which yielded differential binding of prostate cancer specific transcription factors on the SNP-SNAP array, with prostate cancer incidence. This technology can assay millions of SNPs and multiple transcription factors simultaneously, thus representing one of the first methods to evaluate SNP functionality in a high throughput manner. Our SNP- SNAP technology, by virtue of the array custom design and ability to examine millions of DNA permutations, is also broadly applicable to any cancer type and disease model.

项目总结