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

基本信息

批准号：
10359184
负责人：
Robert Mark Vaughan
金额：
$ 8.72万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10359184
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 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 Fibrinogen 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 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 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 base 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 training structural biology therapeutic target tumor tumor growth tumor progression two-dimensional ubiquitin-protein ligase undergraduate research

项目摘要

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.

项目摘要结节性硬化症复合物（TSC）是一种遗传综合征，使患者易于肿瘤形成，并且经常在婴儿期被诊断出。脑部病变，包括亚依赖型巨细胞星形胶质细胞瘤（SEGA）和皮质块茎，发生在约20％的TSC患者中，并且由于存在极端的表型异质性，因此仍然具有挑战性。为了更好地理解和监视哪些患者可能会出现严重的脑部病变以及相关的耐药性癫痫，该项目旨在了解TSC的基因型 - 表型关系。我假设TSC患者的肿瘤负担的严重程度与特定遗传修饰剂中突变（可以通过）突变有关。我的目标是（1）表征与SEGA和皮质块茎相关的遗传修饰剂，（2）在DNA损伤修复基因中建立了我们在TSC患者中已经鉴定出的DNA损伤修复基因的生物学后果。这里的研究和培训计划旨在使我接受转化和临床研究，对患者数据的分析，CRISPR/CAS9基因组编辑的实施，使用两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对于我作为独立研究人员的未来职业至关重要。