Mechanisms of Monocytosis in Obesity:Implications for Cardiovascular Disease

简介(申请人提供)：拟议的职业发展计划旨在使PI具备独特的技能，扩大知识库和研究经验，以满足成为一名生产性研究人员的短期目标和成为肥胖、糖尿病和心血管疾病(CVD)领域单核/巨噬细胞生物学的独立研究员的长期目标。该计划将在肯塔基大学(英国)实施，这是一所以强大的心血管疾病研究项目而闻名的机构。PI将由心血管内科主任苏珊·史密斯博士指导，巴恩斯特布朗糖尿病和肥胖中心主任菲尔·克恩博士共同指导。该计划建议利用PI最近从哥伦比亚大学的研究中获得的见解来探索单核细胞增多症、脂肪组织(AT)炎症及其对动脉粥样硬化的影响之间的关系。PI发现，中性粒细胞衍生的损伤相关分子模式(DAMP)，如S100A8/A9，推动骨髓生成，严重影响糖尿病患者动脉粥样硬化病变的消退。此外，他发现肥胖小鼠模型白色AT中S100A8和S100A9的mRNA表达显著增加。然而，与I型糖尿病小鼠模型不同的是，肥胖模型中S100A8和S100A9的循环水平既不增加，也不受高血糖的驱动。为什么S100A8和S100A9在AT中增加，以及它们是否参与肥胖性单核细胞增多症，目前尚不清楚。这个项目的总体目标是了解肥胖如何影响循环中WBC的数量和表型，特别是单核细胞，进而影响动脉生物学。我们将使用小鼠模型来研究导致这些人类异常的机制，为旨在减少有害的湿气或细胞因子的治疗策略开发一种“概念证明”，并评估该策略是否会改变小鼠模型的动脉粥样硬化。最后，我们将确定在老鼠身上形成的洞察力是否与人类的变化相关。具体目标1将确定AT中驱动肥胖症患者单核细胞产生的细胞和信号分子的来源。为此，我们还将确定肥胖的影响和体重减轻对骨髓生成的影响，并表征肥胖小鼠模型中循环单核细胞的表型。具体目标2将确定介导肥胖诱导的单核细胞增多症的过程和信号通路。具体目标3将评估肥胖诱导的单核细胞增多症对动脉粥样硬化病变消退的影响。总而言之，该项目的成果将为肥胖症中单核细胞增多的原因和后果提供新的见解。

DESCRIPTION (provided by applicant): The proposed career development plan is designed to equip the PI with unique skill sets, expand knowledge base and research experience to meet the short-term goal of becoming a productive researcher and a long- term goal of becoming an independent investigator in monocyte/macrophage biology in the areas of obesity, diabetes mellitus and cardiovascular disease (CVD). The plan will be carried out at the University of Kentucky (UK), an institution that is renowned for its strong CVD research program. The PI will be mentored by Dr. Susan Smyth, the Chief of Cardiovascular Medicine and co-mentored by Dr. Phil Kern, the Director of Barnstable Brown Diabetes and Obesity Center. The plan proposes to explore the relationship between monocytosis, adipose tissue (AT) inflammation and its impact on atherosclerosis using insights the PI recently gained from studies at Columbia University. The PI has found that neutrophil-derived damage associated molecular patterns (DAMP), such as S100A8/A9 drives myelopoiesis and severely affects atherosclerotic lesion regression in diabetes. Further, he found a dramatic increase in the mRNA expression of both S100A8 and S100A9 in white AT from obese mouse models. However, unlike in type I diabetic mouse models, the circulating levels of S100A8 and S100A9 in obese models are neither increased nor driven by hyperglycemia. Why S100A8 and S100A9 are increased in AT and whether they are involved in obesity-induced monocytosis is not clear. The overall goal of this project is to understand how obesity affects the number and phenotype of circulating WBCs, particularly the monocytes and, in turn, arterial biology. We will use mouse models to study the mechanisms driving these human abnormalities, develop a "proof of concept" for a treatment strategy aimed at reducing the offending DAMPs or cytokines, and assess whether this strategy will alter atherosclerosis in mouse models. Finally, we will determine whether insights developed in mice correlate with changes in humans. Specific Aim 1 will determine the sources of cells and signaling molecules in AT that drives monocyte production in obesity. In this aim, we will also determine the effect of adiposity and impact of weight loss on myelopoiesis and characterize the phenotype of circulating monocytes in mouse models of obesity. Specific Aim 2 will identify the processes and signaling pathways that mediate obesity-induced monocytosis. Specific Aim 3 will assess the impact of obesity-induced monocytosis on atherosclerotic lesion regression. Collectively the outcomes of this project will provide novel insights into the causes and consequences of enhanced monocytosis in obesity.