The role of NF-kB in ATM Survival

描述（由申请人提供）：在过去几年中，肥胖已成为一个主要的全球性健康问题，可导致胰岛素抵抗（IR）和2型糖尿病。脂肪组织（AT）中的巨噬细胞炎症被认为有助于肥胖个体中IR的发展。研究表明，抗炎巨噬细胞在瘦AT中更普遍，而炎性巨噬细胞在肥胖AT中更普遍。许多实验室主要集中在招募新的巨噬细胞进入肥胖AT作为AT巨噬细胞（ATM）数量增加的机制。然而，巨噬细胞的保留也可能是其累积的机制。有趣的是，没有人关注ATM凋亡的缺陷作为AT中巨噬细胞保留/积累的机制。以往的研究表明，ATM细胞凋亡确实发生在肥胖小鼠。此外，我们实验室的初步数据表明，与肥胖小鼠相比，ATM在瘦小鼠中更容易发生凋亡。确定肥胖小鼠中ATM存活率增加的机制可能会导致发现降低ATM含量的可行靶点。转录因子NF-？B参与介导许多细胞类型中的促存活以及促炎基因表达，并在ATM中表达。增加NF-？ATM中的B活化可以作为其在肥胖小鼠中存活的介导因子。因此，我们假设NF-？B活化有助于肥胖AT中炎性巨噬细胞的存活。为了确定NF-kB在肥胖小鼠ATM生存中的作用，BCL 2促生存蛋白和NF-κ B的表达差异？将评估瘦小鼠和肥胖小鼠ATM中的B活化。此外，我们将确定如何抑制或激活NF-？B调节瘦小鼠和肥胖小鼠的ATM存活。

DESCRIPTION (provided by applicant): Obesity has become a major worldwide health issue over the past few years that can lead to insulin resistance (IR) and type 2 diabetes. Macrophage inflammation in adipose tissue (AT) is thought to contribute to the development of IR in obese individuals. Studies have shown that anti-inflammatory macrophages are more prevalent in lean AT, whereas inflammatory macrophages are more prevalent in obese AT. Many labs have largely focused on recruitment of new macrophages into obese AT as a mechanism of increased AT macrophage (ATM) number. However, retention of macrophages may also serve as a mechanism for their accrual. Interestingly, no one has focused on a defect in ATM apoptosis as a mechanism responsible for retention/accumulation of macrophages in AT. Previous studies demonstrate that ATM apoptosis does occur in obese mice. In addition, preliminary data from our lab suggest that ATMs are more prone to apoptosis in lean compared to obese mice. Determining the mechanisms involved in increased ATM survival in obese mice may lead to the discovery of viable targets for decreasing ATM content. The transcription factor, NF-?B, is involved in mediating pro-survival as well as pro-inflammatory gene expression in many cell types and is expressed in ATMs. Increased NF-?B activation in ATMs could serve as a mediator of their survival in obese mice. Therefore, we hypothesize that NF-?B activation contributes to survival of inflammatory macrophages in obese AT. To determine the role of NF-kB in ATM survival in obese mice, differences in the expression of BCL2 pro-survival proteins and NF-?B activation in ATMs of lean and obese mice will be assessed. In addition, we will determine how inhibition or activation of NF-?B modulates ATM survival in lean and obese mice.