Mechanisms of Monocytosis in Obesity:Implications for Cardiovascular Disease

肥胖中单核细胞增多的机制：对心血管疾病的影响

• 批准号: 8679403
• 负责人: Prabhakara Reddy Nagareddy
• 金额: $ 8.99万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8679403
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Area; Arterial Fatty Streak; Atherosclerosis; Automobile Driving; Biology; Blood; Body Weight decreased; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Comorbidity; Development; Development Plans; Diabetes Mellitus; Diabetic mouse; Diet; Environment; Epidemic; Functional disorder; Genetic; Goals; Health; Human; Hyperglycemia; Inflammation; Inflammatory; Institution; Interleukin-1; Intervention; Kentucky; Lesion; Leukocytes; Ligands; Link; Mediating; Mediator of activation protein; Medicine; Mentors; Metabolic syndrome; Modeling; Molecular; Monocytosis; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; Natural Immunity; Necrosis; Necrosis Induction; Neutrophilia; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity associated cardiovascular disease; Outcome; Patients; Pattern; Phenotype; Plasma; Play; Process; Production; Recruitment Activity; Reporting; Research; Research Personnel; Research Proposals; Resolution; Role; S100A8 gene; S100A9 gene; Severities; Signal Pathway; Signal Transduction; Signaling Molecule; Source; Stimulus; TLR4 gene; Techniques; Time; Training; Travel; Universities; cardiovascular disorder risk; career development; cell type; cytokine; design; experience; feeding; insight; knowledge base; mRNA Expression; macrophage; meetings; monocyte; mouse model; neutrophil; novel; progenitor; programs; public health relevance; receptor; response; skills; treatment strategy; type I diabetic

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.

描述（由申请人提供）：拟议的职业发展计划旨在为PI配备独特的技能，扩大知识库和研究经验，以实现成为一名富有成效的研究人员的短期目标，以及成为肥胖症，糖尿病和心脏血管疾病（CVD）中单核细胞/巨噬细胞生物学的独立研究者的长期目标。该计划将在肯塔基大学（英国）进行，该机构以其强大的CVD研究计划而闻名。 PI将由心血管医学负责人Susan Smyth博士指导，并由Barnstable Brown Diabetes and Obesity Center主任Phil Kern博士进行指导。该计划建议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，利用PI最近从哥伦比亚大学研究中获得的见解。 PI发现中性粒细胞损害相关的分子模式（潮湿），例如S100A8/A9驱动骨髓病，严重影响糖尿病的动脉粥样硬化病变回归。此外，他发现来自肥胖小鼠模型的白色s100a8和s100a9的mRNA表达都显着增加。但是，与I型糖尿病小鼠模型不同，肥胖模型中S100A8和S100A9的循环水平既没有增加也不由高血糖驱动。为什么S100A8和S100A9在AT中增加以及它们是否参与肥胖引起的单核细胞增多症。该项目的总体目标是了解肥胖如何影响循环WBC的数量和表型，尤其是单核细胞以及动脉生物学。我们将使用小鼠模型来研究驱动这些人类异常的机制，为旨在减少危险湿或细胞因子的治疗策略开发“概念证明”，并评估该策略是否会改变小鼠模型中的动脉粥样硬化。最后，我们将确定小鼠中发展的见解是否与人类变化相关。具体的目标1将确定细胞的来源和在该细胞中驱动肥胖中单核细胞产生的源。在此目的中，我们还将确定肥胖对骨髓运动的影响，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回归的影响。该项目的总体结果将为肥胖中单核细胞增多的原因和后果提供新的见解。