PREDOCTORAL FELLOWSHIPS FOR STUDENTS WITH DISABILITIES

描述(由申请人提供)：虽然肥胖与胰岛素抵抗和糖尿病有关，但其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)信号通路可能起一定作用。这项建议阐述了JNK1在饮食诱导的肥胖过程中对胰岛素抵抗发展的组织特异性影响。我们的假设是肥胖诱导巨噬细胞特异性JNK，从而导致外周胰岛素抵抗。为了验证这一假说，我们将：(1)检查从a)JNK缺陷小鼠到野生型小鼠的骨髓移植小鼠，(B)将JNK缺陷型小鼠移植到JNK缺陷型小鼠并将其置于高脂饮食中并进行代谢监测，(2)通过使用ATP类似物的JNK激酶来筛选巨噬细胞中JNK底物的磷酸化状态，以及(3)分析胰岛素抵抗巨噬细胞的转录谱。更好地了解巨噬细胞中JNK的分子机制可能会阐明肥胖与胰岛素抵抗和代谢综合征疾病的密切联系。

DESCRIPTION (provided by applicant): 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.