This proposal addresses an important gap in our knowledge and understanding of the role of dendritic cells and innate immunity in immuno-metabolic dysfunction. Increasing evidence indicates that obesity and obesity-induced type 2 diabetes (T2D) is, in large part an inflammatory disorder mediated by both innate and adaptive immunity. At the cellular level, it is well recognized that inflammatory macrophages, designated as M1, play an important role in the low-grade inflammation in adipose tissue during the course of obesity and related metabolic complications including T2D. T lymphocytes, (CD4+, CD8+ and Foxp3+ Treg) and B cells are also found in the adipose tissue and the level of infiltration is correlated with the severity of obesity and metabolic dysfunction. Dendritic cells are central to linking innate and adaptive immune responses, responding through receptors that signal through MyD88, amongst others, to stimulate adaptive immune responses. These cells play a key role upstream of the adaptive immune T and B cells as well as interact with macrophages in early phases of the immune response. However, not much is known about the role of dendritic cells (DCs) in the immunopathogenesis of obesity and its complication T2D and the role of MyD88, an important adaptor protein that controls innate immunity in these metabolic disorders. The current application is designed to address this issue in both animal models of obesity and related T2D as well as patients with these disorders. This will be achieved by using a unique mouse model system of both "gain-of-function" and "loss-of-function" of MyD88 in DCs and the studies in patients with obesity and/or T2D who undergo gastric bypass surgery. Our study will be achieved by a close collaboration between the principal investigator, the co-PI and the collaborator, who are experienced investigators with the unique capacity to bridge basic and clinical science as well as the fields of immunobiology and diabetes/metabolism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100500-01A1
Application #
8761742
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Abraham, Kristin M
Project Start
2014-08-15
Project End
2018-05-31
Budget Start
2014-08-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$356,381
Indirect Cost
$138,881
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520