CYTOKINE GENE THERAPY AND OBESITY

描述：拟议的项目有两个主要目标：1)表明 多效性细胞因子白血病抑制因子(LIF) 重组腺相关病毒(RAAV)载体中枢或外周均可 控制正常瘦大鼠较长时间的体重增长， 具有特定遗传缺陷的肥胖大鼠，以及饮食诱导肥胖(DIO) 瘦素抵抗的大鼠；和2)证明这种效应是由 影响细胞内下游信号转导通路的变化 涉及STAT-3(信号转导和转录激活因子)和SOCS-3 (细胞因子信号抑制因子)与激素诱导的类似 下丘脑神经元中的瘦素。具体来说，一系列重组 携带人LIF基因的重组腺相关病毒载体的构建 将构建和测试强大的构成和可诱导的启动子 在瘦SD大鼠、肥胖的Zucker FA/FA以及DIO啮齿动物中 模特们。早些时候，研究人员已经表明，编码1)的rAAV 脂类激素瘦素；2)睫状神经营养因子可以 成功地用于维持瘦素抵抗肥胖症患者的体重 Zucker大鼠。同样，他们已经证明了rAAV-hLIF是 给药能有效抑制SD大鼠正常体重增加 在中央。在这里，Zolotukhin博士和他的同事们提议评估一种 几种不同载体传递途径的激光诱导因子的厌氧效应 瘦身和肥胖大鼠模型伴随着对脑内神经递质激活的分析 导致体重丢失的下丘脑信号转导通路。结果是 这些研究不仅将确定基因疗法是否安全可行 控制体重的长期治疗策略，但也可能使LIF成为一种 瘦素抵抗模型中有效瘦素替代物的研究 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.