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Determining the effect of DNMT3A loss on the competitive fitness of mutant cells in somatic mosaicism

确定 DNMT3A 缺失对体细胞嵌合突变细胞竞争适应性的影响

基本信息

批准号：
10603960
负责人：
Sarah Marie Waldvogel
金额：
$ 4.71万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-20 至 2026-12-19
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10603960
关键词：
Address Adipocytes Affect Apoptosis Biology Blood Cell Culture System Cell Differentiation process Cell Line Cells Childhood Chimera organism DNA Modification Methylases DNMT3a DNMT3a mutation Development Developmental Gene Disadvantaged Disease Drug or chemical Tissue Distribution ES Cell Line Embryo Embryonic Development Environment Epigenetic Process Epithelium Exhibits Failure Flow Cytometry Fluorescence-Activated Cell Sorting Future Gene Cluster Gene Mutation Genes Genetic Counseling Germ Layers Goals Growth Hematopoietic stem cells Heterozygote Human Human body Image Cytometry In Vitro Individual Inherited Intellectual functioning disability Intestines Knock-out Knockout Mice Knowledge Location Loss of Heterozygosity LoxP-flanked allele Malignant Neoplasms Medical center Medicine Mesenchymal Messenger RNA Methylation Microinjections Modeling Mosaicism Mus Mutation Neurons Organism Parents Pathogenesis Pathologic Patient Care Patients Pediatric Oncologist Phenotype Population Predisposition Proteins Rahman Syndrome Recurrence Reporter Research Risk Role Sampling Scientist Seizures Seminal Shapes Somatic Mutation Syndrome System Technology Testing Texas Tissues Training blastomere structure cancer predisposition career cell type clinical care college constitutive expression design developmental disease differential expression embryo cell embryonic stem cell fitness in vivo insight intestinal epithelium leukemia loss of function loss of function mutation mRNA Differential Displays mosaic mouse model mutant neural novel overexpression pediatrician postnatal public health relevance self-renewal stem cell population stem cells success transcriptome sequencing trend

项目摘要

PROJECT SUMMARY/ABSTRACT Epigenetic dysregulation is a shared mechanism of many developmental disorders. One such disorder, Tatton-Brown-Rahman Syndrome (TBRS), results from heterozygous mutations in the de novo DNA methyltransferase, DNMT3A. TBRS is characterized by intellectual disability, seizures, overgrowth, multiple developmental abnormalities, and a predisposition to various malignancies. Since its 2014 discovery, more than 200 patients with TBRS have been identified. In the blood, patients with TBRS exhibit decreased methylation at developmental gene clusters, and abnormal tissue development in patients with TBRS results in numerous lifelong complications. However, a major gap in knowledge is that the mechanism by which DNMT3A regulates development of non-hematopoietic tissues remains unknown. Our lab has identified two individuals who exhibit a mixture of wild-type and DNMT3A-mutant cells throughout their bodies, such that they are constitutive mosaics. The distribution of mutant cells is highly variable across their tissues, and concomitant analysis of wild-type and mutant cells reveals methylation differences that suggest a role of DNMT3A in tissue development. We hypothesize that DNMT3A wild-type and mutant cells have distinct propensities to form different tissues when directly competed with one another. Understanding which tissues are favored by mutant cells in somatic mosaics will lend insight into the pathogenesis of TBRS. To test our central hypothesis, I have established a novel mouse model of somatic mosaicism. I will use this mouse and an in vitro cell culture system to address two aims: 1) I will investigate the effect of Dnmt3a loss on the differentiation capacity of specific stem cell populations, and 2) I will investigate the downstream contribution of Dnmt3a-mutant versus wild-type cells to post-natal mouse tissues. Our long-term goal is to identify tissues in which DNMT3A loss confers a selective advantage or disadvantage and to explore the mechanism of this differential tissue composition. The project is designed to prepare me for a career as an academic pediatric oncologist specializing in inherited developmental and cancer predisposition syndromes. The Goodell lab has made seminal discoveries in DNMT3A biology and has a long track-record of successful MSTP trainees. The collaborative training environment at Baylor College of Medicine, with its state-of-the-art technology cores and prime location in the Texas Medical Center will facilitate the success of this project. In the future, the results of these studies may inform the clinical care of patients with TBRS by identifying tissues in which a DNMT3A mutation is poorly tolerated. The studies may also help to inform genetic counselling of parents of patients with TBRS about their risk of recurrence by characterizing expansion or depletion of DNMT3A-mutant cells in gonadal tissues. Finally, these results will expand our understanding of how mutant cells that appear in early embryogenesis compete with wild-type cells to shape normal and disordered development.

项目总结/文摘