Characterizing genetic modifiers in tumor burden of Tuberous Sclerosis Complex

项目总结 结节性硬化症(TSC)是一种易导致肿瘤形成的遗传综合征，通常在婴儿时期被诊断出来。脑部病变，包括室管膜下巨细胞星形细胞瘤(SEGA)和皮质结节，发生在约20%的TSC患者中，由于存在极端的表型异质性，因此仍然具有挑战性。为了更好地了解和监测哪些患者可能发生严重的脑部病变和相关的治疗难治性癫痫，本项目旨在了解TSC的基因-表型关系。我假设TSC患者的肿瘤负担的严重程度与特定的遗传修饰物的突变有关(并且可以预测)。我的目标是(1)表征与SEGA和皮质结节相关的遗传修饰物，以及(2)确定我们在TSC患者中发现的DNA损伤修复基因突变的生物学后果。这里的研究和培训计划旨在让我接触到翻译和临床研究、患者组学数据分析、CRISPR/Cas9基因组编辑的实施、二维和三维人类细胞模型的使用以及代谢概况。这些技能和我在这个职业阶段所接受的培训对我未来作为一名独立研究员的职业生涯将是必不可少的。

PROJECT SUMMARY Tuberous Sclerosis Complex (TSC) is a genetic syndrome that predisposes patients to tumor formation and is often diagnosed during infancy. Brain lesions, including subependymal giant cell astrocytoma (SEGA) and cortical tubers, occur in ~20% of TSC patients and remain challenging to manage as there is extreme phenotypic heterogeneity. In order to better understand and surveil which patients are likely to develop severe brain lesions and associated treatment-resistant epilepsy, this project aims to understand the genotype-phenotype relationships of TSC. I hypothesize that the severity of tumor burden in TSC patients is associated with (and can be predicted by) mutations in specific genetic modifiers. I aim to (1) characterize genetic modifiers that associate with SEGA and cortical tubers and (2) establish biological consequences of mutations in DNA damage repair genes that we have identified in patients with TSC. The research and training plans here are designed to expose me to translational and clinical research studies, analysis of patient -omics data, implementation of CRISPR/Cas9 genome editing, use of two- and three-dimensional human cell models, and metabolic profiling. These skills and the training I receive in this career phase will be essential for my future career as an independent researcher.