CYTOKINE GENE THERAPY AND OBESITY

描述：拟议的项目有两个主要目标：1）表明， 多效细胞因子白血病抑制因子（LIF）通过 重组腺相关病毒（rAAV）载体，可 在正常瘦大鼠中长时间控制体重（BW）增加， 肥胖大鼠与特定的遗传缺陷，并在饮食诱导肥胖（DIO） 瘦素抗性大鼠;和2）证明这种作用是由以下因素引起的： 影响细胞内下游信号转导途径的变化 涉及STAT-3（信号转导和转录激活因子）和SOCS-3 （细胞因子信号转导抑制因子）类似于激素诱导的那些 瘦素在下丘脑神经元中的表达。具体来说，一系列重组 携带人LIF cDNA的腺相关病毒（rAAV）载体， 一个强大的组成型和诱导型启动子将被构建和测试 在瘦Sprague-Dawley（SD）、肥胖Zucker fa/fa以及DIO啮齿类大鼠中 模型早些时候，研究人员已经表明，rAAV编码1） 2）睫状神经营养因子（CNTF）可 成功用于维持瘦型和瘦素抵抗型肥胖患者的体重fa/fa Zucker大鼠分别。同样，他们已经证明rAAV-hLIF是 有效抑制SD大鼠的正常体重增加， 中心。在这里，Zolotukhin博士和他的同事们建议评估一个 LIF使用不同的载体递送途径在几种细胞中的促凋亡作用 瘦的和肥胖的大鼠模型，同时分析激活 导致BW损失的下丘脑信号转导途径。结果 这些研究将不仅决定基因治疗是否安全和可行， 长期的治疗策略，以控制体重，但也可能建立LIF作为一个 瘦素抵抗模型中有效的瘦素替代物 环境（DIO）或遗传因素，并阐明对下丘脑的影响 神经化学信号和相关的代谢紊乱。

DESCRIPTION: The proposed project has two main objectives: 1) to show that the pleiotropic cytokine leukemia inhibitory factor (LIF) administered via a recombinant adeno-associated virus (rAAV) vector centrally or peripherally, can control body weight (BW) gain for extended periods of time in normal lean rats, obese rats with specific genetic defects, and in diet-induced obese (DIO) leptin-resistant rats; and 2) to demonstrate that this effect is derived by affecting a change in intracellular downstream signal transduction pathways involving STAT-3 (signal transducer and activator of transcription) and SOCS-3 (suppressor of cytokine signaling) similar to those induced by the hormone leptin in hypothalamic neurons. Specifically, a series of recombinant adeno-associated virus (rAAV) vectors carrying human LIF cDNA under the control of a strong constitutive and inducible promoters will be constructed and tested in lean Sprague-Dawley (SD), obese Zucker fa/fa, as well as in DIO rodent rat models. Earlier the investigators have shown that a rAAV encoding 1) the lipostatic hormone leptin; and 2) the ciliary neurotrophic factor (CNTF) could be successfully used to maintain BW in lean and leptin-resistant obese fa/fa Zucker rats respectively. Likewise, they have demonstrated that a rAAV-hLIF is efficient to restrain the normal BW gain in SD rats when administered centrally. Here Dr. Zolotukhin and his colleagues propose to evaluate an anorexigenic effect of LIF using different routes of vector delivery in several lean and obese rat models concomitant with the analysis of activation of hypothalamic signal transduction pathways leading to the BW loss. The results of these studies will not only determine if gene therapy is a safe and viable long-term therapeutic strategy to control BW, but may also establish LIF as an effective leptin substitute in models of leptin resistance caused by environmental (DIO) or genetic factors and elucidate the impact on hypothalamic neurochemical signaling and associated metabolic disorders.