CYTOKINE AND HORMONE INTERACTIONS IN COMORBIDITY OF AIDS

描述（由申请人提供）：贫血、中性粒细胞减少、瘦体质丧失 艾滋病患者消瘦的质量和死亡率均与升高 促炎细胞因子TNF α和IL-1 β的水平。艾滋病患者 通常给予12周的高剂量重组 人生长激素增加血浆IGF-I，瘦肌肉质量和质量 生活然而，造血细胞和肌肉细胞对 据记录，这些患者的IGF-I存在缺陷。中央 本申请假设是TNF α和IL-1 β负责 诱导IGF-I受体抵抗状态，这不仅有助于 肌肉萎缩，而且还导致艾滋病的贫血和中性粒细胞减少。IGF-I靶点 造血骨髓祖细胞和肌肉成肌细胞，在这里，我们 假设IGF-I受体抵抗的分子机制是 艾滋病患者的消瘦是由促炎细胞因子引起的。目标1将 测试IGF-I通过阻断 丝氨酸蛋白酶的半胱天冬酶家族的激活，以及这是否是 被TNFa抑制。目标2关注的是 酪氨酸磷酸化IGF-I受体，包括胰岛素受体 底物-1（IRS-1）、IRS-2、PI 3-激酶和Akt。目标3将确定 促炎细胞因子抑制关键的IGF-I增殖信号，包括 Shc、EFK 1/2、AFX叉头转录因子和细胞周期蛋白依赖性激酶 抑制剂27.最后，目标4将扩展这些结果与骨髓 祖细胞转化为成肌细胞。初步结果显示，低 在消瘦的艾滋病患者中发现的TNF α和IL-1 β的血液浓度抑制了 IGF-I促进蛋白质合成和分化为 肌管这一目标也将测试新的想法，神经酰胺，一个调解人 TNF α和IL-1 β的作用，诱导IGF-I受体的抵抗， 在肌肉成肌细胞中。需要这些研究来了解 消耗性艾滋病患者促炎细胞因子的临床相关浓度 患者损害了两个细胞上主要激素受体的功能能力， 免疫和肌肉成肌细胞。

DESCRIPTION (provided by applicant): The anemia, neutropenia, loss of lean body mass and mortality of AIDS patients with wasting are associated with elevated levels of the proinflammatory cytokines TNFalpha and IL-1beta. AIDS patients with wasting are often given a 12- week therapy with very high doses of recombinant human growth hormone to increase plasma IGF-I, lean muscle mass and quality of life. However, the responsiveness of both hematopoietic and muscle cells to IGF-I has been documented to be defective in these patients. The central hypothesis of this application is that TNFalpha and IL-lbeta are responsible for inducing a state of IGF-I receptor resistance, which contributes to not only muscle wasting but also to the anemia and neutropenia of AIDS. IGF-I targets both hematopoietic myeloid progenitor cells and muscle myoblasts, and here we hypothesize that the molecular mechanism for IGF-I receptor resistance in wasting AIDS patients is caused by proinflammatory cytokines. Objective 1 will test the idea that IGF-I promotes promyeloid cell survival by blocking activation of the caspase family of serine proteases and whether this is inhibited by TNFa. Objective 2 focuses on the survival promoting activity of the tyrosine phosphorylated IGF-I receptor, including insulin-receptor substrate- 1 (IRS-1), IRS-2, PI 3-kinase and Akt. Objective 3 will determine if proinflammatory cytokines inhibit key IGF-I proliferative signals, including Shc, EFK1/2, AFX forkhead transcription factors and the cyclin-dependent kinase inhibitor 27. Finally, objective 4 will extend these results with myeloid progenitor cells to muscle myoblasts. Preliminary results indicate that low blood concentrations of TNFalpha and IL-1beta found in wasting AIDS patients inhibit the ability of IGF-I to promote both protein synthesis and differentiation into myotubes. This objective will also test the new idea that ceramide, a mediator of the actions of both TNFalpha and IL-1beta, induces resistance of the IGF-I receptor in muscle myoblasts. These studies are needed to understand how clinically-relevant concentrations of proinflammatory cytokines in wasting AIDS patients impair the functional ability of a major hormone receptor on both immune and muscle myoblast cells.