PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

尽管众所周知，肥胖与胰岛素抵抗和糖尿病有关，但潜在的 机制尚不清楚。本实验室最近的研究结果表明，c-jun氨基末端激酶(Jnk) 信号通路可能起到一定作用。这项建议解决了JNK1在组织特异性作用方面的问题 饮食诱导肥胖过程中胰岛素抵抗的发展。我们的假设是肥胖会导致 巨噬细胞特异性JNK，导致外周胰岛素抵抗。为了验证这一假设，我们将：(1) 检查从JNK缺陷小鼠到野生型小鼠的骨髓移植的小鼠 B)野生型小鼠转化为JNK缺陷小鼠，并将被置于高脂肪饮食中并进行代谢监测， (2)通过使用JNK激酶筛选巨噬细胞中JNK底物的磷酸化状态 使用ATP类似物，以及(3)分析胰岛素抵抗巨噬细胞的转录图谱。更好的 了解巨噬细胞中JNK的分子机制可能解释肥胖的强烈 与胰岛素抵抗和代谢综合征疾病的相关性。

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.