Genome Integrative Pathway Modeling of Diabetic Atherosclerosis

描述（由申请人提供）：既往无冠心病（CHD）的糖尿病患者的血管性死亡风险与CHD患者一样高。该项目的目标是通过开发先进的统计分析和新的途径建模能力和技术，基于从动物疾病进展模型收集的微阵列数据，并结合各种功能和基因组数据库资源，探索和发现糖尿病致动脉粥样硬化途径的新的和更完整的调节机制。遵循完善的动物模型的不同糖尿病进展条件的微阵列分析实验将被经济有效地执行，以获得其致动脉粥样硬化途径条件的全基因组基因表达信息（从内脏脂肪组织来源的脂肪细胞和巨噬细胞测量）。我们将仔细研究致动脉粥样硬化的途径机制，特别是与12/15-LO和PPARg相关的机制，由于它们在动脉粥样硬化中的关键生理作用，它们已成为我们主要途径研究的目标。特别是，后者已被确定为治疗II型糖尿病患者心血管并发症的主要药理学靶点之一。我们的具体目标是：1）发现致动脉粥样硬化途径基因，特别是在糖尿病动脉粥样硬化进展的不同阶段与12/15-LO和PPARg相关的基因，通过开发和应用先进的统计分析方法对不同糖尿病动物模型条件下的微阵列数据进行少量重复，2）建立12/15-LO基因表达和功能信息的形式化语言框架及其基因组信息数据库，PPARg和其他致动脉粥样硬化基因，这些基因将从糖尿病动物模型的时间进程微阵列数据中鉴定，并且是已知其在动脉粥样硬化中的功能和机制的基因，以及3）发现糖尿病中新的致动脉粥样硬化途径机制，尤其是与12/15-LO和PPARg相关的基因。这些研究的新发现将直接有益于动脉粥样硬化性心血管疾病的诊断和治疗。我们的GIPaM技术还将大大增强生物医学科学其他领域的途径发现/建模能力。

DESCRIPTION (provided by applicant): Diabetes without previous coronary heart disease (CHD) carries a lifetime risk of vascular death as high as that for people with CHD. The goal of this project is to explore and discover novel and more complete regulation mechanisms of atherogenic pathways in diabetes by developing advanced statistical analysis and novel pathway modeling capabilities and techniques based on microarray data collected from animal disease progression models and combined with various functional and genomic database resources. Microarray profiling experiments that follow different diabetic progression conditions of well-established animal models will be cost-effectively executed to obtain genome-wide gene expression information for their atherogenic pathway conditions (measured from visceral fat tissue-derived adipocytes and macrophages). We will carefully examine the atherogenic pathway mechanisms, especially those associated with 12/15-LO and PPARg, which have been targeted by our primary pathway investigation due to their critical physiological roles in atherosclerosis. In particular, the latter has been identified as one of main pharmacological targets for treating cardiovascular complications among type II diabetes patients. Our specific aims are to: 1) discover atherogenic pathway genes, especially relevant to 12/15-LO and PPARg at different stages of diabetic atherosclerosis progression by developing and applying advanced statistical analysis approaches to microarray data on different diabetic animal-model conditions with a small number of replicates, 2) develop a formal language (FL) framework and its genomic information database for various expression and functional information of 12/15-LO, PPARg and other atherogenic genes that will be identified from the time-course microarray data of diabetic animal models and for the genes known for their functions and mechanisms in atherosclerosis, and 3) discover novel atherogenic pathway mechanisms in diabetes, especially those associated with 12/15-LO and PPARg by developing and applying genome integrative pathway modeling (GIPaM) technology. Novel findings from these investigations will directly benefit the diagnosis and treatment of atherosclerotic cardiovascular disease. Our GIPaM technology will also greatly enhance pathway discovery/modeling capability in other fields of the biomedical science.