Themis (for "Thymocyte expressed molecule involved in selection") is a recently- discovered gene and protein that is highly expressed in immature thymocytes, and is also expressed at a lower level in mature T cells. It is a member of a small gene family of unknown function. Themis-deficient mice become obese and develop glucose intolerance and increased serum insulin, suggesting a relationship between Themis expression and prevention of the inflammation of adipose tissue that leads to metabolic syndrome and type II diabetes (T2D). T cells have recently been shown to be important in this process. Moreover, Themis was identified by genomics as showing a causal relationship to serum insulin level, with a protective effect against T2D. This proposal will investigate how expression of Themis in T cells of different lineages affects T cell involvement in adipose inflammation in response to obesity, and the metabolic syndrome that precedes T2D. It will test how the metabolic syndrome and development of T2D is exacerbated by loss of Themis, and the mechanism of action and specific T cell subsets involved.

Public Health Relevance

The epidemic of obesity and Type II diabetes are becoming extremely important factors to the public health of the US and other developed nations. This project aims to understand the role of T cells in the initiation of the metabolic syndrome that leads to type II diabetes using a new mouse model.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK094173-02
Application #
8438403
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Abraham, Kristin M
Project Start
2012-03-05
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$228,584
Indirect Cost
$107,959
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Fu, Guo; Rybakin, Vasily; Brzostek, Joanna et al. (2014) Fine-tuning T cell receptor signaling to control T cell development. Trends Immunol 35:311-8
Fu, Guo; Casas, Javier; Rigaud, Stephanie et al. (2013) Themis sets the signal threshold for positive and negative selection in T-cell development. Nature 504:441-5