Nuclear Receptor Signaling

Nuclear hormone receptors constitute a superfamily of ligandactivated transcription factors with diverse roles in development and homeostasis..

Work by our group is contributing to the definition of a role for nuclear receptors in lipid metabolism and inflammatory responses in macrophages. We are interested in the roles of PPARs (peroxisome proliferator-activated receptors) and RXRs (retinoid X receptors) in two areas: chronic inflammatory diseases and the homeostasis of adult stem cells.

We have found that myeloid-specific PPARg or RXRa knockout (KO) mice develop chronic renal inflammation and autoantibodies to nuclear antigens, a phenotype that resembles the nephritis seen in human systemic lupus erythematosus. This phenotype is caused by the impaired clearance of apoptotic cells by the knockout macrophages. These defects eventually lead to the development of cardiac hypertrophy, and we are currently trying to understand how the lack of PPARs and RXRs leads to this condition.

Our research into adult stem cells addresses the roles of RXRs and PPARs in the differentiation, proliferation and selfrenewal of hematopoietic stem cells in vitro and in vivo. Emerging evidence suggests that nuclear receptors regulate the decision between maintenance of stemness or differentiation in embryonic stem cells and tissue-specific adult stem cells. We have generated hematopoietic-specific PPARg and RXRa,b-knockout mice, and have embarked on a research program to define the role of these nuclear receptors in the differentiation of bone marrow stem cells into diverse cell populations, including cardiomyocytes, adipocytes and osteoclasts.