Mechanisms of hematopoietic stem cell activation in obesity

肥胖造血干细胞激活机制

• 批准号: 9271955
• 负责人: Kanakadurga Singer
• 金额: $ 16.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271955
• 关键词: Adipose tissue; Age; American; Animal Model; Area; Asthma; Atherosclerosis; Autoimmune Process; Basic Science; Biological Assay; Blood; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; C-reactive protein; Cardiovascular Diseases; Cell Compartmentation; Cell Differentiation process; Cells; Cellular biology; Child; Childhood; Chimera organism; Cholesterol; Chronic; Clinical; Collaborations; Complex; Data; Development; Developmental Biology; Diabetes Mellitus; Diet; Dietary Fatty Acid; Disease; Doctor of Philosophy; Endocrinologist; Endocrinology; Energy Intake; Environment; Epidemic; Evaluation; Event; Expenditure; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Funding; Future; Gender; Generations; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; High Fat Diet; Human; Hypertension; IL6 gene; ITGAX gene; Immune; Immunology; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Knockout Mice; Knowledge; Lead; Leukocytes; Link; Liver diseases; Macrophage Activation; Malignant Neoplasms; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Michigan; Modeling; Morbidity - disease rate; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Myelopoiesis; Nutritional; Obese Mice; Obesity; Obesity associated disease; Overnutrition; Pathologic; Pathway interactions; Physicians; Prevention; Process; Production; Publications; Race; Research; Research Personnel; Research Proposals; Role; Saturated Fatty Acids; Scientist; Signal Pathway; Signal Transduction; Source; Stem cells; Supervision; TLR4 gene; TNF gene; Testing; Therapeutic; Thinness; Tissues; Training; Transplantation; United States; Universities; Unsaturated Fatty Acids; Visceral; base; career; cytokine; diabetic; glucose metabolism; in vivo; inflammatory marker; lipid metabolism; macrophage; medical schools; monocyte; mouse model; neutrophil; novel; nutrient metabolism; obesity in children; obesity treatment; progenitor; public health relevance; skills; stem cell biology; stem cell population; success

 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.

 描述（适用提供）：在美国，肥胖越来越普遍。从能量摄入到并发症（例如代谢综合征）的细胞动力学是复杂的，包括炎症细胞的激活（元炎症）。肥胖性脂肪组织中的髓样（单核细胞，中性粒细胞，巨噬细胞）炎症增加，循环单核细胞的增加有助于代谢和心血管疾病的发展，但这种感染的起源尚不清楚。提出这一研究问题需要一个经过独特训练的个人来理解感染与新陈代谢之间的界面。适当的是一名儿科内分泌学家，他积极治疗肥胖的糖尿病和糖尿病前儿童。为了成为具有元炎症专业知识的物理科学家，候选人将实现以下培训目标：1）进一步2）在使用肥胖模型时发展专业知识，以评估葡萄糖和脂质代谢。 2）在小鼠模型中，在评估造血干细胞（HSC）（HSC）和实验免疫学范式方面的专业知识。 3）开发领导独立的基础科学研究实验室所需的技能，其中包括对实验室中的技术和心理学员的招聘和监督。 4）发展成为一位成功的独立物理科学家，这是通过独立资助的成功合作，演示，出版物和成功的证明。为了实现这些目标，辛格博士已经收集了一群新陈代谢专家（Carey Lumeng MD博士学位），HSCS的免疫学和细胞和发育生物学（Doug Engel PhD和Ivan Maillard MD Phd）来监督这项培训。完成这项培训将有助于在小儿肥胖症的背景下成为具有注射和代谢综合征专业知识的独立研究者的长期职业目标。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来促进该计划， 肥胖和干细胞生物学。该提案的科学目标是研究中心的假设，即饮食引起的肥胖会导致促进髓样分化的HSC的先天改变，并促进炎症性巨噬细胞的产生，从而有助于组织特定的炎症。该方向的理由是基于初步观察，即造血干细胞增加并偏向肥胖的髓样祖细胞。研究建议非常重要，因为它具有鉴定元炎症中新的调节步骤，并提供与肥胖相关疾病进行干预的新领域。该提案的特定科学目的是1）确定肥胖期间长期造血干细胞髓样分化的饮食脂肪酸。目标2）确定Toll样受体4在肥胖引起的HSC激活中的作用。这些科学目的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在小鼠对象模型中养分代谢的评估的专业知识。肥胖引起的感染和造血干细胞生物学专家提供的指导将最大程度地提高应用在这些领域之间的界面上成功的物理科学家的潜力。