Fetal/Postnatal Regulation of GH Receptor Expression

超出所提供的空间。生长激素受体（GHR）的表达和功能对于垂体生长激素（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着关键的作用。GH/GHR在DM肾病发病机制中的直接作用得到了使用GH和GH拮抗剂转基因小鼠、总GHR基因敲除小鼠和使用pegvisomant药理学阻断GHR的研究的支持。这些研究表明，功能性GHR的缺乏赋予了对DM肾病的保护作用。我们的实验室专注于了解GH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结局的新治疗靶点。我们最近的研究已经建立了导致糖尿病GHR基因失调的分子机制。我们已经确定了脂肪酸（FA）作为一种特定的代谢信号，转导DM对GHR基因表达的影响，并确定了肾小球足细胞作为GH在肾脏中作用的潜在靶点。我们建议通过追求以下特定目标来扩展这些初步观察结果：特定目标1测试了FA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确定和表征一种潜在的新型反式作用因子，其在FA对GHR表达的影响的转导中发挥作用。我们还建议测试的子假设，脂肪酸通过Toll受体抑制GHR表达的影响，并增加氧化应激。特定目的2检验了以下假设：GHR基因表达的组织特异性失调伴随肝脏GHR表达的消除以及伴随的GHR表达在肾脏中的保留在DM肾脏并发症的发病机制中起关键作用。将通过分析足细胞靶向GHR基因缺失对DM肾病的影响来检验这一假设。总之，继发于GHR表达失调的GH作用异常在DM肾病的发病机制中起作用。GHR表达的主要控制在转录水平。我们已经确定了改变DM中GHR基因表达的分子机制。深入了解这些机制将为制定新的预防和治疗策略以改变糖尿病肾病的结局提供基础。性能现场=

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===========================================