IFN gamma and other modifiers of kidney disease in TSC

IFN γ 和 TSC 中肾脏疾病的其他调节剂

• 批准号: 6987180
• 负责人: SANDRA L DABORA
• 金额: $ 33.11万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987180
• 关键词: antineoplastics; athymic mouse; clinical research; disease /disorder model; family genetics; genetic mapping; human tissue; interferon gamma; kidney disorder; kidney neoplasms; laboratory mouse; tissue /cell culture; tuberous sclerosis; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Renal disease is an important cause of morbidity in tuberous sclerosis complex (TSC), a Mendelian disorder with autosomal dominant inheritance. TSC is a tumor suppressor gene disorder characterized by the development of benign tumors (hamartomas) in multiple organs including the kidneys. Kidney angiomyolipomas are benign tumors consisting of blood vessels, fat cells and smooth muscle cells, and they occur in approximately 75% of TSC patients over the age of 5 years old. Kidney cysts are also common and occur in about 25% of TSC patients. TSC is a genetic disorder with high penetrance but variable expression. Although the variability in expression is not entirely understood, there is recent evidence that some of the variability in renal disease may be explained by modifier genes. It has been shown that high levels of interferon-gamma in TSC mouse models significantly reduce the severity of renal disease in these animals. It has also been demonstrated that a high expressing allele of interferon-gamma is associated with a decreased frequency of kidney angiomyolipomas in a population of patients with TSC2 mutations. TSC is an excellent model disease for investigating the role of modifier genes in genetic disorders causing renal disease. The goal of the projects outlined below will be to further investigate the role of interferon- gamma as a modifier of renal disease in TSC using mouse models, in vitro studies, and genotype/phenotype studies in a large TSC population. Because of the TSC mouse models available for these studies as well as our prior work on genotype/phenotype studies for TSC, we are in a unique position to further define the role of interferon-gamma in this disorder. Furthermore, because interferon-gamma is an approved drug, we will direct significant effort towards testing interferon-gamma as a prevention or treatment agent in preclinical studies using the TSC mouse models. We anticipate that this work will not only improve our understanding of the role of interferon-gamma as a genetic modifier of kidney disease in TSC, but will also contribute to the development of novel therapeutic strategies for TSC renal disease and related disorders as well as lead to the identification of novel genetic modifiers.

描述（由申请人提供）：肾病是结节性硬化症（TSC）发病的重要原因，结节性硬化症是一种具有常染色体显性遗传的孟德尔疾病。 TSC 是一种肿瘤抑制基因疾病，其特征是在包括肾脏在内的多个器官中出现良性肿瘤（错构瘤）。肾血管平滑肌脂肪瘤是由血管、脂肪细胞和平滑肌细胞组成的良性肿瘤，约 75% 的 5 岁以上 TSC 患者发生这种肿瘤。肾囊肿也很常见，约 25% 的 TSC 患者出现肾囊肿。 TSC 是一种外显率高但表达变异的遗传性疾病。 尽管表达的变异性尚不完全清楚，但最近有证据表明肾脏疾病的一些变异性可以通过修饰基因来解释。研究表明，TSC 小鼠模型中高水平的干扰素-γ 可显着降低这些动物肾脏疾病的严重程度。研究还表明，干扰素-γ 的高表达等位基因与 TSC2 突变患者群体中肾血管平滑肌脂肪瘤发生率降低相关。 TSC 是研究修饰基因在引起肾脏疾病的遗传性疾病中的作用的绝佳模型疾病。下面列出的项目的目标是使用小鼠模型、体外研究和大量 TSC 群体的基因型/表型研究，进一步研究干扰素 γ 作为 TSC 肾病调节剂的作用。由于可用于这些研究的 TSC 小鼠模型以及我们之前对 TSC 基因型/表型研究的工作，我们处于独特的地位，可以进一步确定干扰素-γ 在这种疾病中的作用。此外，由于干扰素 γ 是一种已批准的药物，因此我们将投入大量精力，在使用 TSC 小鼠模型的临床前研究中测试干扰素 γ 作为预防或治疗剂的作用。我们预计这项工作不仅将提高我们对干扰素-γ作为 TSC 肾脏疾病遗传修饰剂的作用的理解，而且还将有助于开发 TSC 肾脏疾病和相关疾病的新治疗策略以及铅识别新型遗传修饰剂。