IFN gamma and other modifiers of kidney disease in TSC

描述（由申请方提供）：肾脏疾病是结节性硬化症（TSC）发病的重要原因，TSC是一种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发生良性肿瘤（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患者发生肾血管平滑肌脂肪瘤。肾囊肿也很常见，约25%的TSC患者会发生肾囊肿。TSC是一种高表达的遗传性疾病。 虽然表达的变异性还不完全清楚，但最近有证据表明，肾脏疾病的一些变异性可能是由修饰基因解释的。已经表明，TSC小鼠模型中高水平的干扰素-γ显著降低这些动物中肾脏疾病的严重程度。也已经证明，干扰素-γ的高表达等位基因与TSC 2突变患者群体中肾血管平滑肌脂肪瘤的频率降低相关。 TSC是研究修饰基因在导致肾脏疾病的遗传性疾病中的作用的极好模型疾病。下面概述的项目的目标将是使用小鼠模型、体外研究和大型TSC人群中的基因型/表型研究进一步研究干扰素-γ作为TSC中肾病修饰剂的作用。由于可用于这些研究的TSC小鼠模型以及我们先前对TSC的基因型/表型研究的工作，我们处于独特的位置，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是一种批准的药物，我们将在使用TSC小鼠模型的临床前研究中将干扰素-γ作为预防或治疗剂进行显著的测试。我们预计，这项工作不仅将提高我们的理解干扰素-γ作为遗传修饰剂的肾脏疾病在TSC的作用，但也将有助于开发新的治疗策略TSC肾脏疾病和相关疾病，以及导致识别新的遗传修饰剂。

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.