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.

Public Health Relevance

The goal of this application is to train Kanakadurga Singer MD, a Pediatric Endocrinologist, in the evaluation of hematopoiesis during obesity by investigating how stem-cell changes induced by obesity contribute to metabolic dysfunction. The training plan will be carried out under the guidance of a mentorship team composed of experts in metabolism, inflammation, and hematopoietic stem cell biology with the proposal goal of understanding the mechanism by which stem cells are stimulated during dietary challenge. There is a critical need for this information to further the knowledge for future therapeutic strategies and accomplishing the proposed aims will also generate a pediatric researcher with the necessary training in immunometabolism to approach the critical issues effecting children with obesity and its sequelae.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK101755-04
Application #
9507823
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Spain, Lisa M
Project Start
2015-09-01
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zamarron, Brian F; Mergian, Taleen A; Cho, Kae Won et al. (2017) Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice. Diabetes 66:392-406
Wang, Sophia Y; Andrews, Chris A; Gardner, Thomas W et al. (2017) Ophthalmic Screening Patterns Among Youths With Diabetes Enrolled in a Large US Managed Care Network. JAMA Ophthalmol 135:432-438
Singer, Kanakadurga; Lumeng, Carey N (2017) The initiation of metabolic inflammation in childhood obesity. J Clin Invest 127:65-73
Scheller, Erica L; Khoury, Basma; Moller, Kayla L et al. (2016) Changes in Skeletal Integrity and Marrow Adiposity during High-Fat Diet and after Weight Loss. Front Endocrinol (Lausanne) 7:102