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Function of RUNX1 in diverse Down syndrome tissues

RUNX1在多种唐氏综合症组织中的功能

基本信息

批准号：
10853906
负责人：
Mary A Allen
金额：
$ 19.15万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10853906
关键词：
Address Administrative Supplement Adult Affect Alternative Splicing Award Basic Science Binding Biological Assay Blood Blood Cells Cell Differentiation process Cell Line Cells Chromatin Chromatin Remodeling Factor Chromosome 21 DNA DNA Binding DNA Binding Domain DNA-Directed RNA Polymerase Data Defect Development Disease Down Syndrome Embryonic Development Equilibrium GATA1 gene Gene Dosage Genetic Transcription Grant Hematological Disease Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells High Prevalence Histones Homeostasis Incidence Individual Knock-out Life Link Mediating Megakaryocytopoieses Methods Molecular Motivation Mutation Myeloid Leukemia Outcome Parents Pattern Pharmaceutical Preparations Phenotype Play Protein Isoforms RNA Polymerase II RNA Splicing RUNX1 gene Recruitment Activity Reporting Risk Role Specific qualifier value Tissues Transactivation Transcription Coactivator Trisomy Variant Work acute myeloid leukemia 1 protein blastomere structure cell type cost dosage embryo cell high reward high risk improved induced pluripotent stem cell insight leukemia loss of function mutation novel overexpression postnatal recruit transcription factor

项目摘要

Project Summary Parent Proposal: RUNX1, also known as Acute Myeloid Leukemia 1 protein (AML1), is a transcription factor that plays a critical function in the specification of the hematopoietic lineage during embryogenesis and is required for normal megakaryopoiesis throughout the postnatal life. The RUNX1 gene is localized to band q22.12 of chromosome 21, which is triplicated in individuals with Trisomy 21 (T21). For this reason, an extra copy of RUNX1 has been proposed to play relevant roles in the hematological alterations associated with Down syndrome (DS). We seek to decipher the contribution of RUNX1 to the phenotypes seen in individuals with Down syndrome. Since transcription factors bind to DNA and alter RNA polymerase activity, we will determine if those two functions of RUNX1 are altered in Down syndrome-derived cells. We will also define if drugs that increase or inhibit RUNX1 function behave differently in cells with an extra copy of chromosome 21. Finally, we will ascertain how much of the altered blood differentiation seen in Down syndrome is caused by RUNX1 by ‘normalizing’ RUNX1 gene dosage in a trisomy background (e.g., two copies in a trisomy cell line). We will then analyze the differentiation of iPSCs into embryoid bodies and blood cells. Collectively this work will shed important insights into the functions of RUNX1 and how it is altered in Trisomy 21. Supplement Project Summary: A recent report by Gialesaki et al. (March 2023) established a critical role for RUNX1 alternative splicing and isoform imbalance -rather than overall expression- as a major driver of Down syndrome-associated myeloid leukemia (DS-ML). These findings have important implications on most of the specific aims of our proposal. Therefore, we should partially modify some of our sub-aims to assess the relevance of RUNX1 splicing equilibrium on the different outcomes of DS-derived iPSC and lymphoblastoid cell differentiation and homeostasis. A second motivation for this supplement applies exclusively to Aim 3. Here we orginally proposed to normalize RUNX1 gene dosage by knocking-out one copy in the T21 +/+/− iPSC line (T21 RUNX1 ). We now propose alternative strategies to overcome such obstacles and incorporate the isoform-specific analyses just mentioned. This Administrative Supplement addresses Component 1: A targeted high risk - high reward basic science study that is relevant to Leukemia risk in Down syndrome. Moreover this supplement will significantly improve the scientific significance of the project by contributing to a better understanding of the underlying mechanisms that govern hematological alterations in individuals with T21.

项目总结