Mechanisms of hematopoietic stem cell activation in obesity

 描述(申请人提供)：肥胖症在美国越来越普遍。从能量摄入到代谢综合征等并发症的细胞动力学是复杂的，包括炎症细胞的激活(间化)。肥胖患者脂肪组织中髓系(单核细胞、中性粒细胞、巨噬细胞)炎症的增加以及循环中单核细胞的增加有助于代谢和心血管疾病的发展，但这种炎症的起源尚不清楚。推进这一研究问题需要一个在理解炎症和新陈代谢之间的界面方面接受过独特培训的人。申请者是一名儿科内分泌科医生，积极治疗肥胖、糖尿病和糖尿病前期儿童。为了成为一名在代谢方面具有专业知识的内科科学家，应聘者将完成以下培训目标：1)进一步发展利用肥胖小鼠模型来评估葡萄糖和脂肪代谢的专业知识。2)发展在小鼠模型中评估造血干细胞(HSC)和实验免疫学范例方面的专业知识。3)培养领导独立基础科学研究实验室所需的技能，包括雇用和监督技术人员，并在实验室指导受训人员。4)发展成为一名成功的独立内科科学家，成功的合作、演讲、出版物和成功的独立资助就是明证。为了实现这些目标，Singer博士召集了一批新陈代谢专家(Carey Lumeng医学博士)、免疫学专家以及造血干细胞的细胞和发育生物学专家(Doug Engel博士和Ivan Maillard博士)来监督此次培训。完成这项培训将有助于实现长期的职业目标，即成为一名在儿童肥胖背景下的炎症和代谢综合征方面具有专业知识的独立调查员。密歇根大学医学院的环境非常适合通过其糖尿病研究中心促进这一计划， 肥胖症和干细胞生物学。这项提议的科学目标是研究中枢假说，即饮食诱导的肥胖导致HSC的先天变化，促进髓系分化，并促进炎性巨噬细胞的产生，从而促进组织特异性炎症。这一方向的理论基础是基于初步观察，即肥胖患者的造血干细胞增加并向髓系祖细胞倾斜。这项研究建议具有重要意义，因为它有能力确定代谢过程中新的调节步骤，并为肥胖相关疾病的干预提供新的领域。这项建议的具体科学目标是1)确定在肥胖期间促进长期造血干细胞髓系分化的饮食脂肪酸。目的2)探讨Toll样受体4在肥胖诱导的肝星状细胞活化中的作用。这些科学目标的完成将提供所需的培训，以获得干细胞评估、骨髓嵌合体的产生和分析以及肥胖小鼠模型的营养代谢评估方面的专业知识。由肥胖引起的炎症和造血干细胞生物学专家提供的指导将使申请者在这些领域之间的接口上成为一名成功的内科科学家的潜力最大化。

 DESCRIPTION (provided by applicant): Obesity is increasingly prevalent in the United States. The cellular dynamics that lead from energy intake to complications such as metabolic syndrome are complex and include the activation of inflammatory cells (metainflammation). Increased myeloid (monocyte, neutrophil, macrophage) inflammation in adipose tissue with obesity as well as an increase in circulating monocytes contributes to the development of metabolic and cardiovascular diseases, but the origins of this inflammation are not well understood. Advancing this research question requires an individual uniquely trained in understanding the interface between inflammation and metabolism. The applicant is a Pediatric Endocrinologist who actively treats obese diabetic and pre-diabetic children. To become a physician-scientist with expertise in metainflammation, the candidate will accomplish the following training goals: 1) To further develop expertise in the use of mouse models of obesity to assess glucose and lipid metabolism. 2) To develop expertise in the assessment of hematopoietic stem cells (HSC) and paradigms of experimental immunology in mouse models. 3) To develop the skills necessary to lead an independent basic science research lab, which includes hiring and supervision of technicians and mentoring trainees in the lab. 4) To develop into a successful independent physician scientist, as evidenced by successful collaborations, presentations, publications, and success with independent funding. To accomplish these goals, Dr. Singer has gathered a group of experts in metabolism (Carey Lumeng MD PhD), immunology and cell and developmental biology of HSCs (Doug Engel PhD and Ivan Maillard MD PhD) to oversee this training. Accomplishing this training will facilitate the long-term career goal of becoming an independent investigator with expertise in inflammation and metabolic syndrome in the context of pediatric obesity. The environment at the University of Michigan Medical School is uniquely suited to facilitate this plan through its research centers in diabetes, obesity, and stem cell biology. The scientific goals of this proposal are to investigate the centra hypothesis that diet-induced obesity leads to innate alterations in HSCs promoting myeloid differentiation, and promoting production of inflammatory macrophages that contribute to tissue specific inflammation. The rationale for this direction is based on preliminary observations that hematopoietic stem cells are increased and skewed towards myeloid progenitors with obesity. This research proposal is significant as it has the capacity to identify novel regulated steps in metainflammation along with providing novel areas for intervention in obesity-associated diseases. The specific scientific aims of this proposal are 1) To identify the dietary fatty acids that augment long term hematopoietic stem cell myeloid differentiation during obesity. Aim 2) To determine the role of toll-like receptor 4 in obesity-induced activation of HSCs. Completion of these scientific aims will provide the training required to gain expertise in stem cell assessments, generation and analysis of bone marrow chimeras, and evaluation of nutrient metabolism in mouse models of obesity. The guidance provided by experts in obesity-induced inflammation and hematopoietic stem cell biology will maximize the potential for the applicant to be a successful physician scientist at the interface between these fields.