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）：拟定的职业发展计划旨在为PI提供独特的技能组合，扩展知识基础和研究经验，以实现成为高效研究人员的短期目标和成为肥胖、糖尿病和心血管疾病（CVD）领域单核细胞/巨噬细胞生物学独立研究者的长期目标。该计划将在肯塔基州大学（英国）进行，该大学以其强大的CVD研究计划而闻名。PI将由心血管内科主任Susan Smyth博士指导，并由Barnstable Brown糖尿病和肥胖中心主任Phil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，嗜中性粒细胞衍生的损伤相关分子模式（DAMP），如S100 A8/A9，驱动骨髓生成，并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的白色AT中S100 A8和S100 A9的mRNA表达显著增加。然而，与I型糖尿病小鼠模型不同，肥胖模型中S100 A8和S100 A9的循环水平既不增加也不受高血糖症的驱动。为什么S100 A8和S100 A9在AT中增加，以及它们是否参与肥胖诱导的单核细胞增多症尚不清楚。该项目的总体目标是了解肥胖如何影响循环白细胞的数量和表型，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驱动这些人类异常的机制，为旨在减少冒犯性DAMP或细胞因子的治疗策略开发“概念验证”，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，我们将确定在小鼠中开发的见解是否与人类的变化相关。具体目标1将确定AT中驱动肥胖症中单核细胞产生的细胞和信号分子的来源。在这个目标中，我们还将确定肥胖的影响和体重减轻对骨髓生成的影响，并描述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对动脉粥样硬化病变消退的影响。总的来说，该项目的结果将为肥胖症中单核细胞增多症的原因和后果提供新的见解。