IFN gamma and other modifiers of kidney disease in TSC

描述(申请人提供)：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紊乱，其特征是发生在包括肾脏在内的多个器官的良性肿瘤(错构瘤)。肾血管平滑肌脂肪瘤是一种由血管、脂肪细胞和平滑肌细胞组成的良性肿瘤，约75%的TSC患者在5岁以上。肾囊肿也很常见，约25%的TSC患者会发生。TSC是一种高外显性但表达可变的遗传性疾病。虽然表达的可变性并不完全清楚，但最近的证据表明，肾脏疾病中的一些可变性可能是由修饰基因解释的。研究表明，在TSC小鼠模型中，高水平的干扰素-γ显著降低了这些动物的肾脏疾病的严重程度。研究还表明，在TSC2突变患者中，干扰素-γ的高表达等位基因与肾脏血管肌脂肪瘤的发生率降低有关。 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一个很好的模型疾病。下面概述的项目的目标将是利用小鼠模型、体外研究以及在TSC大人群中的基因/表型研究，进一步研究干扰素-γ作为TSC肾脏疾病修饰物的作用。由于可用于这些研究的TSC小鼠模型，以及我们之前在TSC的基因型/表型研究方面的工作，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-伽马是一种被批准的药物，我们将在使用TSC小鼠模型的临床前研究中，将大量努力用于测试干扰素-伽马作为预防或治疗剂。我们预计，这项工作不仅将提高我们对干扰素-γ作为肾脏疾病遗传修饰物在TSC中的作用的理解，还将有助于开发TSC肾脏疾病和相关疾病的新治疗策略，并导致新的遗传修饰物的发现。

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.