Multidimensional Molecular Biomarkers of MultiOrgan Dysfunction after MCS Therapy

描述（由申请人提供）：心力衰竭（HF）影响美国近600万人。目前，机械循环支持装置（MCS）治疗是不适合心脏移植的晚期心力衰竭（AdHF）患者的唯一选择。MCS越来越多地提供给患有AdHF和多种合并症的高度复杂患者。多种免疫功能异常描述了AdHF综合征和危重患者。尽管可以挽救生命，但炎症机制可能使患者处于发展多器官功能障碍综合征（MOD）的风险中，其特征在于全身炎症反应的持续激活、器官灌注减少和终末器官损伤。我们认为，低灌注器官和组织中改变的白细胞和内皮细胞生物学之间的相互作用使器官功能障碍恶化并激活免疫系统，导致不受控制的全身炎症反应和MOD，这是MCS手术后AdHF患者最常见的死亡原因。微阵列技术允许实施全基因组分子诊断。综合基因组学和系统生物学方法为开发新一代分子工具作为强大的生物标志物奠定了基础。流式细胞术是一种稳健的方法，其允许通过鉴定细胞表面蛋白、细胞内磷蛋白和细胞因子以及其他功能读数来表征复杂混合物（例如血液）中的许多细胞亚群。我们小组的研究确定了MCS后的炎症反应模式，通过外周血单核细胞（PBMC）基因表达进行评估，这些基因表达与MOD程度的增加直接特异性相关。我们的假设是多维分子生物标志物（MMB）改善了对有MOD风险的MCSD患者的评估和选择。MMB结合了多参数免疫细胞流式细胞术，以及使用RNA测序的全基因组转录组分析，其使用基于系统的计算分析在时间依赖性设计中评估。为了检验我们的假设，我们将在MCS接受者中进行一项前瞻性时间依赖性研究，旨在表征（1）MOD后PBMC基因表达的时间模式和（2）MOD后PBMC免疫表型的时间模式，以（3）重建MCS后MOD的时间基因表达-免疫表型程序和（4）测试MMB预测MCS后MOD风险的可行性和初步疗效。该提案的发现将导致新的分子生物标志物的开发，以改善对选择进行MCS的AdHF患者的复杂表型和风险预测的评价。

DESCRIPTION (provided by applicant): Heart failure (HF) affects nearly 6 million people in the United States. Currently, Mechanical Circulatory Support Device (MCS) therapy is the only alternative for patients with advanced heart failure (AdHF) who are not candidates for heart transplantation. MCS is increasingly being offered to highly complex patients with AdHF and multiple comorbidities. Multiple abnormal immune functions describe the AdHF syndrome and the critically ill patient. Despite being life-saving, inflammatory mechanisms may put patients at risk of developing multiorgan dysfunction syndrome (MOD) characterized by persistent activation of the systemic inflammatory response, decreased organ perfusion and end organ damage. We propose that the interaction between altered leukocyte and endothelial cell biology in hypoperfused organs and tissues worsen organ dysfunction and activate the immune system, leading to uncontrolled systemic inflammatory response and MOD, the most common cause of death among patients with AdHF after MCS surgery. Microarray technologies allowed the implementation of genome wide molecular diagnostics. Integrative genomics and systems biological methodologies set the basis to develop a new generation of molecular tools as robust biomarkers. Flow cytometry is a robust methodology that allows for the characterization of many subsets of cells in a complex mixture such as blood by identifying cell-surface proteins, intracellular phosphoproteins and cytokines, as well as other functional readouts. Research by our group identified patterns of inflammatory response after MCS assessed by peripheral blood mononuclear cell (PBMC) gene expression that are directly and specifically related to increasing degrees of MOD. Our hypothesis is that multidimensional molecular biomarkers (MMB) improve the evaluation and selection of patients undergoing MCSD who are at risk of MOD. MMBs incorporate multi-parameter immune cell flow cytometry, and genome wide transcriptome analysis using RNA Sequencing evaluated in a time- dependent design using systems-based computational analysis. To test our hypothesis, we will conduct a prospective time-dependent study in MCS recipients designed to characterize (1) temporal patterns of PBMC gene expression and (2) temporal patterns of PBMC immune phenotypes after MOD to (3) reconstruct the temporal gene expression - immunophenotype program of MOD after MCS and (4) test the feasibility and preliminary efficacy of MMB to predict the risk of MOD after MCS. Discoveries made by this proposal will lead to novel molecular biomarker development for the improved evaluation of complex phenotypes and risk prediction in AdHF patients being selected for MCS.