Analysis of Gene Function by Genome-wide Transcriptional Phenotyping

通过全基因组转录表型分析基因功能

• 批准号: 7858220
• 负责人: GAD SHAULSKY
• 金额: $ 30.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7858220
• 关键词: ATP-Binding Cassette Transporters; Address; Affect; Animal Model; Antineoplastic Agents; Biological Process; Cancer Biology; Cell-Cell Adhesion; Cells; Chemotaxis; Cisplatin; Classification; Collaborations; Communities; Data; Data Analyses; Databases; Diagnosis; Diagnostic; Diagnostic Procedure; Dictyostelium; Disease; Drug Delivery Systems; Funding; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic; Genetic Epistasis; Goals; Health; Human; Laboratories; Laboratory Finding; Mammals; Measures; Metabolism; Methods; Microarray Analysis; Molecular Profiling; Morphology; Mutagenesis; Mutate; Mutation; Pathway Analysis; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Physiological; Research Personnel; Resistance; Sphingosine; Testing; Toxic effect; Yeasts; abstracting; base; cancer diagnosis; comparative; functional genomics; gene discovery; gene function; genome-wide; mutant; outcome forecast; phenomics; programs; response; tool; transcription factor

Global expression profiles are excellent phenotypes. In cancer biology they can be used for diagnosis and prognosis. In yeast and other model organisms they have been used for discovering gene function and drug targets. In the previous funding period we found that expression profiles of Dictyostelium are also useful diagnostics. We also tested and proved the hypothesis that expression profiles can be used as phenotypes for genetic epistasis analysis and pathway construction. In this proposal we will assign function to hundreds of genes by using expression profiles as phenotypes to characterize mutants. We will also test the hypothesis that distinct patterns of global gene expression represent specific, definable biological functions. In a nutshell, we propose that changes in subsets of the expression pattern represent changes in specific biological functions such as cell-cell adhesion or chemotaxis. If this hypothesis were correct, one would be able to identify the specific biological functions that have been affected by mutations or drug treatment, turning the expression profile from an abstract phenotype into a direct diagnostic tool. The applicaiton of this discovery to human health is self evident as it would transform microarray diagnosis of cancer and other diseases from a comparative method into a direct diagnostic method. To reach these goals we will perform microarray analysis of gene expression on several hundred mutants, correlate their expression profiles with other phenotypes, such as chemotaxis, infer which biological functions are represented by which subset of the expression profile and test the functions directly by mutagenesis. In addition, we will analyze selected mutants for specific functions. We will test mutants in 20 of the 66 ABC transporters, all 19 bZIP transcription factors, mutants in a new chemotaxis pathway and mutants with altered sensitivity to the anti-cancer drug cisplatin. Successful completion of these goals will assign function to hundreds of new genes and turn expression profiling into a powerful tool for direct diagnosis of biological function. The data will also be disseminated to the community as a means of expanding the correlation between expression profiles and specific biological functions beyond the scope of this proposal.

全球表达曲线是出色的表型。在癌症生物学中，它们可用于诊断和 预后。在酵母和其他模型生物中，它们已用于发现基因功能和 药物靶标。在上一个资金期间，我们发现Dictyostelium的表达曲线也是 有用的诊断。我们还测试并证明了一个假设，即表达曲线可以用作 用于遗传上毒分析和途径构建的表型。在此建议中，我们将分配功能 通过使用表达谱作为表型来表征突变体的数百个基因。我们还将测试 全球基因表达的不同模式代表特定，可定义的生物学的假设 功能。简而言之，我们提出表达模式子集的变化代表变化 在特定的生物学功能中，例如细胞 - 细胞粘附或趋化性。如果这个假设是正确的，一个 将能够识别受突变或药物影响的特定生物学功能 处理，将表达曲线从抽象表型转化为直接诊断工具。这 申请这一发现的人类健康是自我明显的，因为它会改变微阵列的诊断 癌症和其他比较方法的疾病直接诊断方法。到达这些 目标我们将对数百个突变体上的基因表达进行微阵列分析，并将其关联 具有其他表型的表达谱，例如趋化性，推断哪些生物学功能是 由表达曲线的哪个子集表示，并直接通过诱变来测试功能。在 此外，我们还将分析选定的突变体的特定功能。我们将在66个ABC中的20个中测试突变体 转运蛋白，所有19个BZIP转录因子，新的趋化途径中的突变体和具有的突变体 对抗癌药物顺铂的敏感性改变了。这些目标成功完成将分配 对数百个新基因的功能，并将表达谱分析变成一个有力的工具，用于直接诊断 生物功能。数据也将被传播到社区，以扩大 表达谱与特定生物学功能之间的相关性超出了该建议的范围。