权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of hematopoietic stem cell activation in obesity

肥胖造血干细胞激活机制

基本信息

批准号：
9134736
负责人：
Kanakadurga Singer
金额：
$ 15.53万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/9134736
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 Differentiation process Cells Child Childhood Chimera organism Cholesterol Chronic Clinical Collaborations Complex Data Development Developmental Cell 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 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 progenitor skills stem cell biology stem cell population success

项目摘要

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.