Characterizing genetic modifiers in tumor burden of Tuberous Sclerosis Complex

结节性硬化症肿瘤负荷中基因修饰的特征

• 批准号: 10581654
• 负责人: Robert Mark Vaughan
• 金额: $ 9.16万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581654
• 关键词: 3-Dimensional; Acetylesterase; Area; Basic Science; Binding; Biochemical; Biochemistry; Biological; Biophysics; Brain; CRISPR/Cas technology; Cell Proliferation; Cell model; Cellular biology; Chromatin; Clinical; Clinical Research; Colon; Colorectal Cancer; Complement; DNA; DNA Binding; DNA Ligases; DNA Methylation; DNA Modification Methylases; DNA Repair; DNA biosynthesis; Data; Development; Diagnosis; Disease; Disease Management; Elements; Enzymatic Biochemistry; Epigenetic Process; Epilepsy; Exposure to; Fellowship; Future; Gene Expression Regulation; Genetic; Genetic Diseases; Genetic study; Genomics; Genotype; Goals; Health; Heterogeneity; Histone H3; Histones; Homologous Gene; Human; In Vitro; Intestinal Cancer; Intestines; Invaded; Investments; Lesion; Ligase; Link; Linker DNA; Maintenance; Malignant Neoplasms; Messenger RNA; Metabolic; Metabolism; Methyltransferase; Modeling; Molecular; Mutation; Neoplasm Metastasis; Okazaki fragments; Oncogenic; Oncoproteins; Organoids; Outcome; PHD Finger; Pathogenicity; Patients; Pattern; Phase; Phenotype; Postdoctoral Fellow; Process; Protein Biochemistry; Proteins; Research; Research Personnel; Research Project Grants; Research Training; Resistance; Ring Finger Domain; Role; Severities; Severity of illness; Shapes; Signal Transduction; Subependymal Giant Cell Astrocytoma; Syndrome; Techniques; Technology; Therapeutic; Training; Translational Research; Tuberous Sclerosis; Tumor Burden; Ubiquitin; Up-Regulation; anticancer research; bacterial resistance; cancer cell; cancer type; career; cortical tubers; design; disabling symptom; epigenome; epigenomics; gene repair; genome editing; genome sequencing; in vivo; infancy; insight; interest; microbial; microbiome; microbiome research; microorganism; mouse model; next generation sequencing; personalized medicine; precision medicine; protein function; recruit; research study; screening; skills; structural biology; therapeutic target; tumor; tumor growth; tumor progression; two-dimensional; ubiquitin-protein ligase; undergraduate research

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.

项目摘要 多发性硬化综合征（TSC）是一种遗传综合征，使患者易于形成肿瘤，通常在婴儿期诊断。脑病变，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，并且由于存在极端的表型异质性，仍然具有管理挑战性。为了更好地了解和监测哪些患者可能发展为严重的脑病变和相关的难治性癫痫，本项目旨在了解TSC的基因型-表型关系。我假设TSC患者肿瘤负荷的严重程度与特定遗传修饰因子的突变相关（并且可以通过其预测）。我的目标是（1）表征与SEGA和皮质块茎相关的遗传修饰剂，（2）建立我们在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转化和临床研究，分析患者组学数据，实施CRISPR/Cas9基因组编辑，使用二维和三维人类细胞模型以及代谢分析。这些技能和我在这个职业阶段接受的培训将是我未来作为一名独立研究人员的职业生涯所必需的。