Fetal Postnatal Regulation of Expression of the GH Receptor

胎儿出生后 GH 受体表达的调节

• 批准号: 7384660
• 负责人: Ram K. Menon
• 金额: $ 32.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7384660
• 关键词: Animals; Antioxidants; Award; Back; Carbohydrates; Caring; Cells; Child; Chronic; Clinical Research; Collaborations; Complications of Diabetes Mellitus; Data; Development; Diabetic Angiopathies; Diabetic Nephropathy; Diabetic mouse; Disease; Down-Regulation; Endocrinology; Exons; Fatty Acids; Figs - dietary; Funding; Gastroenterology; Gene Expression; Genetic Transcription; Growth; Growth Hormone Receptor; Hepatic; Hormone Antagonists; Hypopituitarism; Hypothalamic structure; IGF1 gene; Individual; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Kidney; Kidney Diseases; Knockout Mice; Laboratories; Laser coagulation; Life; Ligands; Lipopolysaccharides; Liver; Malnutrition; Mediating; Metabolic; Molecular; Morbidity - disease rate; Mus; Operative Surgical Procedures; Outcome; Oxidative Stress; Pathogenesis; Patients; Pituitary Gland; Play; Proteins; Receptor Gene; Receptor Signaling; Regulation; Research; Retinal Diseases; Role; Secondary to; Sepsis; Signal Pathway; Signal Transduction; Somatotropin; Standards of Weights and Measures; Testing; Tissues; Trans-Activators; Transcript; Transcriptional Activation; Transgenic Mice; Translating; Trauma; Universities; Untranslated Regions; Up-Regulation; Virus; base; feeding; fetal; hormone resistance; infliximab; lipid metabolism; novel; novel therapeutics; pegvisomant; podocyte; postnatal; prevent; proliferative diabetic retinopathy; promoter; protective effect; protein expression; receptor; receptor expression; reconstitution; research study; restoration; therapeutic target; tumor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：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 DM 慢性微血管并发症的发病机制中发挥着关键的许可作用。 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 敲除小鼠以及使用培维索孟对 GHR 的药理学阻断的研究的支持。这些研究表明，功能性 GHR 的缺失对糖尿病肾病具有保护作用。我们的实验室致力于了解 GH 在 DM 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果的新治疗靶点。我们最近的研究已经确定了导致 DM 中 GHR 基因失调的分子机制。我们已经确定脂肪酸 (FA) 是一种特定的代谢信号，可以转导 DM 对 GHR 基因表达的影响，并确定肾小球足细胞是肾脏中 GH 作用的潜在目标。我们建议通过追求以下具体目标来扩展这些初步观察结果：具体目标 1 测试 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鉴定并表征一种潜在的新型反式作用因子，该因子在 FA 对 GHR 表达的影响的转导中发挥作用。我们还建议检验以下子假设：FA 通过 Toll 受体转导其对 GHR 表达的影响并增加氧化应激。具体目标 2 检验了以下假设：GHR 基因表达的组织特异性失调、肝脏 GHR 表达的消除以及伴随的肾脏 GHR 表达的保留在 DM 肾脏并发症的发病机制中起着至关重要的作用。该假设将通过分析足细胞靶向删除 GHR 基因对 DM 肾病的影响来检验。