The role of NF-kB in ATM Survival

描述（由申请人提供）：肥胖在过去几年中已成为一个主要的全球健康问题，可导致胰岛素抵抗（IR）和2型糖尿病。脂肪组织中的巨噬细胞炎症（AT）被认为有助于肥胖个体IR的发展。研究表明，抗炎巨噬细胞在瘦型AT中更为普遍，而炎性巨噬细胞在肥胖型AT中更为普遍。许多实验室主要关注新巨噬细胞募集到肥胖AT，作为AT巨噬细胞（ATM）数量增加的机制。然而，巨噬细胞的滞留也可能是巨噬细胞积累的一种机制。有趣的是，没有人关注ATM细胞凋亡缺陷作为巨噬细胞在AT中保留/积累的机制。先前的研究表明，肥胖小鼠确实会发生ATM细胞凋亡。此外，我们实验室的初步数据表明，与肥胖小鼠相比，瘦小鼠的atm更容易发生细胞凋亡。确定肥胖小鼠ATM存活增加的机制可能导致发现降低ATM含量的可行靶点。转录因子NF-？B，在许多细胞类型中参与介导促生存和促炎症基因表达，并在atm中表达。增加了NF - ?在肥胖小鼠中，atm中的B活化可能是其存活的中介。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存活中的作用，BCL2促存活蛋白和NF-？评估瘦鼠和肥胖鼠atm中B的激活情况。此外，我们将确定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.