DNA methylation markers of Multimorbidity in Aging Humans and Mice

多发性骨髓瘤（MM）是一个公共卫生问题，通常被定义为两种或多种慢性疾病 在老年人中。MM患者因多药、残疾和早产而面临医源性损伤的高风险 死亡，对照顾者的挑战和社会的成本。MM的病理生理学研究 单一的生物标志物或途径的成功有限。此外，没有全面的生物标志物， 以前的经验和初步数据证实了这一假设 存在与MM相关的潜在DNA甲基化（DNAm）生物标志物， 人口水平。此外，在人类组织水平上对MM机制的研究有限 因为道德和后勤上的复杂性被忽视但无可争议的关键，识别DNA标记 与MM小鼠模型相关的研究对于发展我们预测MM的能力至关重要， 进一步阐明其潜在机制。 该提案的总体目标是鉴定人群中MM的DNAm标志物， 小鼠模型，以开发一套全面的工具，用于识别处于风险中的个人。所得 标记将适用于男性和女性个体。使用四个人群队列，我将测试使用 的DNAm标记来预测谁可能发展MM。我将测量细胞特异性DNAm和基因 在基线时无MM的个体和基线时无MM的个体之间， 我将使用MM的动物模型，使用组织病理学方法， 器官研究以定义mm并测量DNAm和同源转录组学（RNA-seq）。的结果 本研究可用于更好地识别和理解导致MM的共享机制。 总的来说，确定“衰老的人类和小鼠中多聚体的DNA甲基化标记”应该允许 老年病学家预测老年人的多发性硬化症，并帮助研究人员进一步了解 多重恐惧的潜在机制。本项目的成果，在未来，可以应用于测试 针对这些机制的干预措施（如二甲双胍）预防和治疗 毫米

Multimorbidity (MM), conventionally defined as two or more chronic diseases, is a public health problem in older adults. MM patients are at high risk of iatrogenesis from polypharmacy, disability, and premature death, with challenges to caregivers and cost to society. The study of the pathophysiology of MM based on single biomarkers or pathways has had limited success. Moreover, there are no comprehensive biomarkers developed to evaluate and predict MM. Previous experience and preliminary data corroborate the hypothesis of the existence of potential DNA methylation (DNAm) biomarkers that are associated with MM at the population level. Additionally, the study of mechanisms of MM at the tissue level in humans have been limited due to ethical and logistical complications. Neglected yet unarguably pivotal, identifying DNAm markers associated with MM mouse models is of paramount importance to develop our capabilities to predict MM and shed more light on its underlying mechanisms. The overarching goal of this proposal is to identify DNAm markers of MM in human populations and mouse models to develop a set of comprehensive tools for the identification of at-risk individuals. The resulting markers will be applicable to both male and female individuals. Using four population cohorts, I will test the use of DNAm markers to predict who is likely develop MM. I will measure how cell specific DNAm and gene expression (RNA-seq) are related and different between individuals who are free of MM at baseline and developed MM and those who remained free of MM. I will use an animal model of MM using histopathology studies of organs to define mm and measure DNAm and cognate transcriptomics (RNA-seq). The results of this study can be used to better identify and understand the shared mechanism(s) that causes MM. Collectively, identifying “DNA methylation markers of multimorbidity in aging humans and mice” should allow geriatricians to predict multimorbidity in older adults and help researchers to further understand the mechanisms underlying multimorbidity. The results of this project, in the future, can be applied to test the effectiveness of interventions such as metformin that target these mechanisms for prevention and treatment of MM.