IFN gamma and other modifiers of kidney disease in TSC

描述（由申请人提供）：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，大约75%的5岁以上的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是一种高外显率但表达可变的遗传病。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以用修饰基因来解释。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肾脏疾病的严重程度。研究还表明，在TSC2突变患者群体中，干扰素γ高表达等位基因与肾血管平滑肌脂肪瘤的发病率降低有关。

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.