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Targeting the NuRD complex for fetal globin induction

靶向 NuRD 复合物诱导胎儿珠蛋白

基本信息

批准号：
10000124
负责人：
NANCY BERLINER
金额：
$ 39.71万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000124
关键词：
ATAC-seq Adult BCL6 gene BTB/POZ Domain Basic Science Binding Binding Sites CRISPR/Cas technology Cell Survival Cells ChIP-seq Chromatin Clinical Code Complex DNA-Binding Proteins Data Defect Development Drug Design Erythroblasts Erythroid Erythroid Cells Exons Fetal Hemoglobin Future Gene Silencing Genes Genetic Transcription Globin Goals Hematopoiesis Hematopoietic Hemoglobin F Disease Hemoglobinopathies Histones Human Knockout Mice Mediating Methylation Modality Molecular Mus Mutagenesis Mutation N-terminal Neoadjuvant Therapy NuRD complex Nucleosomes Pathogenesis Pathway interactions Pharmacology Post-Translational Protein Processing Production Proteins Public Health Publishing Reader Regulation Reporting Repression Repressor Proteins Research Role Scanning Science of genetics Series Sickle Cell Anemia Site Tail Testing Thalassemia Therapeutic Transcription Coactivator Work base beta Globin beta Thalassemia density digital domain mapping fetal gamma Globin gene therapy innovation novel strategies novel therapeutics patient population promoter recruit transcription factor transcriptome

项目摘要

Abstract Hemoglobinopathies, such as sickle cell disease (SCD) and thalassemia, are among the greatest public health concerns in the world. Although new therapeutic modalities, such as gene therapy, are currently being tested, there is a pressing need for pharmacologic approaches to treat general patient populations. Our long-term goal is to develop a compound(s) that induces fetal-type globin (HbF) production by targeting the transcriptional complex regulating globin switching. The objective of this application is to determine molecular mechanisms underlying the LRF-NuRD-mediated γ-globin silencing and identify a mean(s) to target them. Our central hypothesis is that the LRF-containing NuRD complex is a potential target for HbF reactivation therapy. The rationale for the proposed research is that understanding the LRF/NuRD-mediated globin regulation will provide greater understanding of the transcriptional complex regulating γ-globin repression and facilitate development of novel therapeutic strategies for HbF induction therapy. Guided by strong preliminary data, we expect to achieve our objective by pursuing the three specific aims: 1) to determine the molecular basis for γ- globin reactivation in the absence of the LRF/NuRD; 2) to identify a domain(s) of CHD3/4 necessary for γ- globin silencing; and 3) to determine functional significance of LRF/CHD3 interaction in controlling γ-globin silencing. In Aim1, we will employ ChIP-seq and ATAC-seq foot-printing to determine how the NuRD- associated pathways silences γ-globin expression in adult erythroid cells and how γ-globin is induced upon LRF depletion. In Aim2, we will identify a minimal domain(s) of CHD3/4 responsible for γ-globin silencing. To do so, we will perform a functional domain mapping using CRISPR-Cas9 gene mutagenesis. In Aim3, we will determine functional significance of the LRF/CHD3 interaction in controlling γ-globin silencing. Our published work and preliminary data strongly suggest that the NuRD-associated pathways, in which LRF and BCL11A are involved, represent the near entirety of the “globin-switch”. We expect that the combined approaches proposed here will elucidate the role of LRF and the NuRD complex in γ-globin silencing and facilitate development of novel strategies for HbF reactivation therapy for hemoglobinopathies.

摘要

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide CRISPR-Cas9 screen identifies rationally designed combination therapies for CRLF2-rearranged Ph-like ALL

全基因组 CRISPR-Cas9 筛选确定了针对 CRLF2 重排 Ph 样 ALL 的合理设计的联合疗法

DOI：
10.1182/blood.2021012976
发表时间：
2022
期刊：
Blood
影响因子：
20.3
作者：
Sasaki Kensuke;Yamauchi Takuji;Semba Yuichiro;Nogami Jumpei;Imanaga Hiroshi;Terasaki Tatsuya;Nakao Fumihiko;Akahane Koshi;Inukai Takeshi;Verhoeyen Els;Akashi Koichi;Maeda Takahiro
通讯作者：
Maeda Takahiro