Skeletal Muscle Growth Hormone Resistance In Uremia

描述(由申请人提供)：营养不良在慢性肾功能衰竭(CRF)中很常见，对发病率和死亡率有不利影响。导致营养不良和肌肉萎缩的原因是对生长激素(GH)的抵抗。在尿毒症儿童中，这种抵抗力会损害生长。抗性被归因于IGF-I不敏感，理论上是由于生长激素受体(GHR)水平降低，而信号受损是我们最近在动物身上发现的另一个潜在原因。耐药性可以通过高剂量的生长激素来克服，但确实存在一些不良反应的风险。因此，需要新的方法，这将需要更深入地了解生长激素抵抗的机制，这是我们的总体目标。具体目的1.探讨尿毒症对人骨骼肌GHR水平及GH介导的信号转导的影响。我们认为，在终末期CRF患者中，骨骼肌对GH的抵抗不是由于GHR水平降低，而是至少部分原因是GH信号转导的缺陷，这种缺陷因炎症和营养不良而恶化。具体目的2.探讨尿毒症骨骼肌对生长激素诱导的JAK-STAT信号转导和IGF-1基因表达抵抗的机制。具体目的3.确定尿毒症患者是否存在对生长激素非依赖性刺激肌肉中IGF-I基因表达的抵抗，即机械负荷，或者抵抗是否仅限于GH诱导的IGF-I表达。具体目的4.确定，a)炎症是否恶化了对GH信号和作用的抵抗力，b)这是否由肌肉细胞因子表达的增加以及血清细胞因子的增加上调了细胞因子信号的抑制因子所致。这项从正常人和终末期CRF患者的肌肉活检组织进行的体外研究，以及对完整的尿毒症大鼠的体内研究，将为了解尿毒症GH抵抗的机制，包括炎症和营养不良的作用提供新的见解。从长远来看，这些信息应该作为制定新策略的基础，以防止生长激素的丧失或恢复生长激素对生长激素的敏感性。如果成功，这将允许患者对内源性生长激素正常反应，并在需要时对低剂量重组生长激素做出反应，从而改善肾衰竭患者肌肉萎缩的管理。

DESCRIPTION (provided by applicant): Malnutrition is common in chronic renal failure (CRF) and has adverse effects on morbidity and mortality. Contributing to the malnutrition and muscle wasting is resistance to growth hormone (GH). In uremic children, this resistance impairs growth. Resistance has been attributed to IGF-I insensitivity and theoretically to reduced GH receptor (GHR) levels, while impaired signaling is another potential cause that we recently uncovered in animals. Resistance can be overcome by high doses of GH but does carry some risk of adverse effects. Thus new approaches are needed and this will require a deeper understanding of the mechanism of GH resistance, which is our overall goal. Specific Aim 1. To evaluate the effect of uremia on GHR levels and GH mediated signal transduction in human skeletal muscle. We propose that in patients with end stage CRF, skeletal muscle resistance to GH is not due to reduced GHR levels, but is caused at least partly, by a defect in GH signal transduction that is worsened by inflammation and malnutrition. Specific Aim 2. To identify the mechanisms that account for the skeletal muscle resistance to GH induced JAK-STAT signal transduction and IGF-1 gene expression in uremia. Specific aim 3. To determine whether in uremia there is resistance to a GH independent stimulus of IGF-I gene expression in muscle, namely mechanical overload, or whether resistance is limited to GH induced IGF-I expression. Specific Aim 4. To establish, a) whether inflammation worsens the resistance to GH signaling and action and, b) whether this is caused by an increase in muscle cytokine expression that together with increased serum cytokines upregulate the suppressors of cytokine signaling. This study carried out in-vitro with human muscle biopsied from normal subjects and patients with end-stage CRF and in-vivo with intact uremic rats, should provide new insight into the mechanism of GH resistance in uremia, including the role of inflammation and malnutrition. In the long run, this information should serve as a basis for developing new strategies to prevent the loss of, or to restore GH sensitivity to GH. If successful, this would allow patients to respond normally to endogenous GH and when required, to low dose recombinant GH, and thus improve the management of muscle wasting in patients with kidney failure.