Modulation of Age-Related Inflammation by PPAR

项目负责人/主要研究者（末、首、中）：施兴明 衰老与慢性炎症、免疫功能下降、骨丢失和骨髓脂肪有关 积累过氧化物酶体增殖物激活受体-γ（Peroxisome proliferator-activated receptor-gamma，PPARγ）是调节脂肪细胞增殖的关键因子 分化、成熟脂肪细胞存活和功能。过氧化物酶体增殖物激活受体γ在炎症反应中也起重要作用 正如在几种炎性疾病，包括炎性肠病， 过敏性脑脊髓炎和与炎症相关的胰岛素抵抗。因为两 成骨细胞和脂肪细胞来源于共同的骨髓间充质干/祖细胞（MSC），我们 假设敲除MSC中的PPARγ将显著增加骨量并防止衰老- 导致骨质流失。出乎意料的是，我们的研究表明MSC条件性PPARγ基因敲除小鼠（Dermo 1- Cre：PPARγf/f）对老年小鼠的骨仅有中度保护作用，尽管骨密度 在年轻的老鼠身上明显更高。我们发现，PPARγ的缺失降低了多种细胞因子的表达水平， 骨髓基质细胞中干扰素（IFN）刺激的基因，表明PPARγ的缺失受损 IFNγ信号传导，其对于MSC成骨分化和骨形成是重要的。因此， PPARγ KO的增强作用被受损的IFNγ信号传导抵消。此外，我们的数据显示， PPARγ的缺失增加了CD 4 + Th 17 + T细胞亚群，降低了CD 4 + FoxP 3 + T细胞亚群， 血液和骨髓中，这表明在该模型中缺乏PPARγ会加剧炎症。因为 PPARγ和IFNγ的表达受共同转录因子CREB的调节，作用方式完全相反 以这种方式，我们推测，PPARγ基因的缺失撤销了PPARγ启动子与IFNγ的竞争 因此，CREB可自由地用于结合和抑制IFNγ表达。我们将 使用最先进的分子生物学方法测试这一假设，并通过补充 IFNγ对PPARγ KO小鼠的影响，并确定IFNγ信号传导的恢复是否会揭示骨增强 具有抑制PPARγ KO作用，减轻炎症，提高免疫功能。 这项研究的结果将为我们目前对这些机制的理解提供新的线索， PPARγ调节骨、炎症和免疫功能。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码

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