Physiologic Genomics of Pulmonary Hypertension & RVH

描述（由申请人提供）： 分子生物技术的最新突破使人们能够在一次实验中同时测量数千种基因产物。了解这些数据集的复杂性需要在传统分子生物学和计算科学方面进行全面的培训。该指导发展奖的主要目标是为主要研究者（PI）提供必要的培训和环境支持，以发展成为心肺生物学领域的独立计算分子生物学家。这个多学科的奖项将支持PI在生理学，分子生物学，计算生物学和统计学学科的培训，并允许他联合收割机这些工具来研究肺动脉高压和右心室重塑的分子基础。该项目的主要科学目标是通过对全球基因表达谱生成的数据应用严格的统计方法，发现肺动脉高压和右心室肥大（RVH）发病机制中的几个关键遗传途径。将追求两个并行但相互依存的具体目标。目的1将鉴定、表征和确认一组在小鼠肺动脉高压和RVH的发展和消退中至关重要的时间和功能相关的基因。将比较肺动脉高压和RVH的不同小鼠模型，以在这些过程的进展和消退期间寻找共同的遗传途径。此外，肺血管和右心室重构共享几个共同的分子途径的假设将被测试。这种方法将独特地提供全球性的见解复杂的分子过程中激活血管和心室重塑。目标2将允许PI开发和改进计算方法，以规范化原始数据，确定统计学显著的基因表达，并将聚类策略应用于微阵列生成的数据集。在目标2中进行的调查结果将直接应用于目标1中产生的数据。追求计算生物学硕士学位将进一步提高PI成功将复杂数学模型与大规模基因表达谱数据集合并的能力。最终，这个指导研究职业奖将使PI发展成为一个独立的计算分子生物学家，并追求在心肺系统的生理基因组学的学术研究生涯。

DESCRIPTION (provided by applicant): Recent breakthroughs in molecular biotechnology are allowing simultaneous measurements of thousands of gene products in a single experiment. Understanding the complexity of such datasets requires a thorough training in both traditional molecular biology and computational sciences. The primary goal of this mentored development award is to provide the Principal Investigator (PI) the training and environmental support necessary to develop into an independent computational molecular biologist in the field of cardiopulmonary biology. This multidisciplinary award will support the PI's training in the disciplines of physiology, molecular biology, computational biology and statistics, and allow him to combine these tools to investigate the molecular basis of pulmonary hypertension and right ventricular remodeling. The primary scientific goal of this project is to discover several key genetic pathways in the pathogenesis of pulmonary hypertension and right ventricular hypertrophy (RVH) by applying rigorous statistical methods to data generated from global gene expression profiling. Two concurrent but interdependent Specific Aims will be pursued. Aim 1 will identify, characterize and confirm a set of temporally and functionally related genes that are crucial in the development and regression of pulmonary hypertension and RVH in mice. Different mouse models of pulmonary hypertension and RVH will be compared to search for common genetic pathways during both the progression and regression of these processes. Additionally, the hypothesis that pulmonary vascular and right ventricular remodeling share several common molecular pathways will be tested. This approach will uniquely provide global insights into the complex molecular processes activated during vascular and ventricular remodeling. Aim 2 will allow the PI to develop and improve computational methods to normalize raw data, determine statistically significant gene expression, and apply clustering strategies to microarray-generated datasets. The results of investigations undertaken in Aim 2 will be applied directly to data generated in Aim 1. Pursuit of a Master's of Science in Computational Biology will further enhance the PI's ability to successfully merge complex mathematical models with datasets resulting from large-scale gene expression profiling. Ultimately, this mentored research career award will allow the PI to develop into an independent computational molecular biologist and pursue an academic research career in the physiologic genomics of the cardiopulmonary system.