Fetal/Postnatal Regulation of GH Receptor Expression

超出提供的空间。生长激素受体(GHR)的表达和功能对垂体生长激素(GH)的作用至关重要。GH/IGF-1轴在糖尿病慢性微血管并发症的发病机制中起重要作用。GH/GHR在糖尿病肾病发病机制中的直接作用得到了使用GH和GH拮抗剂的转基因小鼠、完全GHR基因敲除小鼠的研究以及使用聚乙二醇胺对GHR的药理阻断的支持。这些研究表明，缺乏功能性GHR对糖尿病肾病具有保护作用。我们的实验室致力于了解生长激素在糖尿病肾病发病机制中作用的分子和细胞基础，并确定将改变糖尿病肾病预后的新的治疗靶点。我们最近的研究已经确定了导致糖尿病患者GHR基因失调的分子机制。我们已经确定脂肪酸(FA)是一种特殊的代谢信号，可以转导DM对GHR基因表达的影响，并已确定肾小球足细胞是GH在肾脏中的潜在作用靶点。我们建议通过追求以下特定目标来扩展这些初步观察：特定目标1检验FAs以组织特异性方式调节DM中GHR基因表达的假设。所提出的实验范式将识别和表征一个潜在的新的反式作用因子(S)，它在FA对GHR表达的影响的转导中发挥作用。我们还建议检验FAs通过Toll受体转导其对GHR表达的影响和增加氧化应激的亚假说。特异性目的2验证了组织特异性GHR基因表达异常、肝脏GHR表达下调和肾脏GHR表达保留在糖尿病肾脏并发症发病机制中的重要作用。这一假说将通过分析足细胞靶向GHR基因缺失在糖尿病肾病中的作用来验证。综上所述，继发于GHR表达异常的GH作用异常在糖尿病肾病的发病机制中起着重要作用。GHR表达的主要调控是在转录水平。我们已经确定了改变糖尿病患者GHR基因表达的分子机制。对这些机制的透彻理解将为制定新的预防和治疗策略以改变糖尿病肾脏疾病的结果提供基础。表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Expression and function of the growth hormone receptor (GHR) is essential for the action of pituitary growth hormone (GH). The GH/IGF-1 axis plays a critical permissive role in the pathogenesis of chronic microvascular complications of DM. A direct role for GH/GHR in the pathogenesis of DM nephropathy is supported by studies using GH and GH-antagonist transgenic mice, total GHR knockout mice, and pharmacological blockade of GHR using pegvisomant. These studies demonstrate that absence of functional GHR confers a protective effect against DM nephropathy. Our laboratory is focused on understanding the molecular and cellular basis for GH's actions in the pathogenesis of DM nephropathy and the identification of novel therapeutic targets that will alter the outcome of diabetic kidney disease. Our recent studies have established the molecular mechanisms resulting in dysregulation of the GHR gene in DM. We have identified fatty acids (FA) as a specific metabolic signal that transduces the effect of DM on GHR gene expression and have identified the glomerular podocyte as potential target of GH action in the kidney. We propose to expand on these preliminary observations by the pursuing the following SPECIFIC AIMS: Specific Aim 1 tests the hypothesis that FAs modulate the expression of the GHR gene expression in DM in a tissue-specific manner. The proposed experimental paradigm will identify and characterize a potentially novel trans-acting factor(s) that plays a role in the transduction of the effect of FA on GHR expression. We also propose to test the sub-hypothesis that FAs transduce their effects on GHR expression via Toll receptors and increase in oxidative stress. Specific Aim 2 tests the hypothesis that tissue-specific dysregulation of GHR gene expression with abrogation of hepatic GHR expression and concomitant retention of expression of GHR in the kidney plays a crucial role in the pathogenesis of renal complications of DM. This hypothesis will be tested by analyzing the effect of podocyte-targeted deletion of the GHR gene on DM nephropathy. In summary, abnormalities in GH action secondary to dysregulation of GHR expression play a role in the pathogenesis of DM nephropathy. The primary control of GHR expression is at the level of transcription. We have identified molecular mechanisms that alter the expression of the GHR gene in DM. A thorough understanding of these mechanisms will provide the foundation for formulating novel preventive and therapeutic strategies to alter the outcome of diabetic kidney disease. PERFORMANCE SITE ========================================Section End===========================================