Functional Characterization of BAFF-induced Genes

描述(申请人提供)：功能基因组学最近的实验正在以前所未有的速度产生新的数据。现在的挑战是将这些大量的新信息整合到对生物系统如何工作的机械性理解中。我们开发了一种生物信息学算法CATEGRIFI，该算法利用基因本体信息，基于协同表达模式对微阵列基因簇进行分类。用CLASTFI软件分析BAFF和CD40L这两种在调节B细胞动态平衡和功能中起重要作用的配体对脾B细胞表达谱芯片数据的影响。对BAFF反应上调的一组探针/基因包含了以前未被表征的高比例序列，这表明BAFF正在诱导一组可能参与新生物过程的新基因的表达。在这个项目中将追求两个总体目标-发展客观的方法来选择和表征以前未确定的基因，以及研究由BAFF控制的调节B淋巴细胞稳态和功能的分子过程。这些目标将通过数据挖掘和假设驱动的实验相结合来实现。该项目的具体目的是通过生物信息学方法和组织表达研究相结合的方法，对受BAFF控制的B细胞反应进行表征，筛选和优先选择未确定特征的探针/基因集，利用生物信息学分析建立候选基因可能的生物学功能的假设，并通过确定相互作用的蛋白质、调查可能的生化活性和测量表达干扰对BAFF介导的B细胞反应的影响来研究候选基因的可能功能。B细胞对BAFF反应的机制研究具有医学意义，因为BAFF调节失调与动物模型和人类自身免疫性疾病的发生有关。

DESCRIPTION (provided by applicant): Recent experimentation in functional genomics is generating new data at an unprecedented rate. The challenge now is to integrate this large amount of new information into a mechanistic understanding of how biological systems work. We have developed a bioinformatics algorithm, CLASSIFI, which uses gene ontology information to classify microarray gene clusters based on coordinated expression patterns. CLASSIFI was used to analyze expression microarray data from splenic B cells stimulated with two ligands, BAFF and CD40L, which play important roles in regulating B cell homeostasis and function. One cluster of probes/genes up-regulated in response to BAFF contains a high proportion of sequences that have not been previously characterized, suggesting that BAFF is inducing the expression of a panel of new genes that may be involved in novel biological processes. Two general goals will be pursued in this project - to develop objective approaches for the selection and characterization of previously uncharacterized genes, and to investigate the molecular processes controlled by BAFF that regulate B lymphocyte homeostasis and function. These goals will be achieved through a combination of data mining and hypothesis-driven experimentation. The specific aims of this project are to characterize the B cell responses controlled by BAFF, to filter and prioritize the uncharacterized probe/gene set through a combination of bioinformatics approaches and tissue expression studies, to develop hypotheses regarding possible biological functions of the candidate genes using bioinformatics analysis, and to investigate possible functions of the candidate genes through a determination of interacting proteins, an investigation of possible biochemical activities and a measurement of expression perturbation effects on BAFF-mediated B cell responses. Mechanistic studies of B cell responses to BAFF are medically relevant since dysregulation of BAFF is associated with the development of autoimmune disease in both animal models and humans.