Program Director/Principal Investigator (Last, First, Middle): Shi, Xing-Ming Aging is associated with chronic inflammation, decline of immune function, bone loss and marrow fat accumulation. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a key factor regulating adipocyte differentiation, mature adipose cell survival and function. PPARγ also plays an important role in inflammation as demonstrated in several mouse models of inflammatory diseases, including inflammatory bowel disease, allergic encephalomyelitis, and insulin resistance which associates with inflammation. Because both osteoblasts and adipocytes derive from a common bone marrow mesenchymal stem/progenitor cell (MSC), we postulated that knockout of PPARγ in MSCs would dramatically increase bone mass and prevent aging- induced bone loss. Unexpectedly, our studies showed that MSC conditional PPARγ knockout mice (Dermo1- Cre:PPARγf/f) had only a moderate protective effect on bone in aged mice, although the bone density was significantly higher in young mice. We found that deletion of PPARγ reduced the expression levels of multiple interferon (IFN)-stimulated genes in bone marrow stromal cells, indicating that deletion of PPARγ impaired IFNγ signaling, which is important for MSC osteogenic differentiation and bone formation. Thus, the bone enhancement effect of PPARγ KO was offset by compromised IFNγ signaling. Furthermore, our data showed that deletion of PPARγ increased CD4+Th17+ subset of T cells and decreased CD4+FoxP3+ Tregs in both blood and bone marrow, suggesting that lack of PPARγ exacerbated inflammation in this model. Because the expression of PPARγ and IFNγ is regulated by a common transcription factor CREB in a completely opposite manner, we hypothesize that deletion of PPARγ gene revokes the competition of PPARγ promoter with IFNγ promoter for CREB binding, thus, making CREBs freely available to bind and inhibit IFNγ expression. We will test this hypothesis using the state-of-the-art molecular biology approaches and validate it by supplementing IFNγ to the PPARγ KO mice and determine if restoration of IFNγ signaling will unmask the bone enhancement effect of PPARγ KO and reduce inflammation and improve immune function. Results of this research will shed new light on our current understanding of the mechanisms by which PPARγ regulates bone, inflammation and immune function. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page