PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

虽然肥胖与胰岛素抵抗和糖尿病有关，但肥胖的潜在原因是胰岛素抵抗。 机制不明。本实验室最近的研究结果表明，c-Jun氨基末端激酶（JNK） 信号通路可能发挥作用。该提案解决了JNK 1对细胞增殖的组织特异性作用。 在饮食诱导的肥胖症期间胰岛素抵抗的发展。我们的假设是肥胖导致 巨噬细胞特异性JNK，其导致外周胰岛素抵抗。为了验证这个假设，我们将：（1） 检查接受从a）JNK缺陷型小鼠到野生型小鼠的骨髓移植的小鼠， B）将野生型小鼠转化为JNK缺陷型小鼠，并将其置于高脂肪饮食中并监测代谢， (2)筛选巨噬细胞中JNK底物的磷酸化状态， 使用ATP类似物，和（3）分析胰岛素抗性巨噬细胞的转录谱。更好的 了解巨噬细胞中JNK的分子机制可能有助于阐明肥胖症的强免疫抑制作用。 与胰岛素抵抗和代谢综合征相关。

Although it is well established that obesity is associated with insulin resistance and diabetes, the underlying mechanisms are unknown. Recent findings in our laboratory indicate that c-Jun amino terminal kinase (JNK) signaling pathway may play a role. This proposal addresses the tissue specific effects of JNK1 on the development of insulin resistance during diet-induced obesity. Our hypothesis is that obesity induces macrophage specific JNK, which leads to peripheral insulin resistance. To test this hypothesis, we will: (1) examine mice that receive a bone marrow transplantation from a) JNK deficient mice into wild type mice and b) wild type mice into JNK deficient mice and will be placed on a high fat diet and monitored metabolically, (2) screen for phosphorylation status of JNK substrates in macrophages by employing a JNK kinase that uses an ATP analogue, and (3) analyze the transcriptional profile of insulin resistant macrophages. A better understanding of the molecular mechanism of JNK in macrophages may elucidate obesity's strong association with insulin resistance and diseases of the metabolic syndrome.