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Reactivation of Gamma Globin Expression in β-Hemoglobinopathies

β 血红蛋白病中伽马珠蛋白表达的重新激活

基本信息

批准号：
10533403
负责人：
Ginette Theresa Balbin-Cuesta
金额：
$ 3.91万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
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：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10533403
关键词：
Binding CD34 gene CDK4 gene CHD4 gene CRISPR screen CRISPR-mediated transcriptional activation Candidate Disease Gene Cell Cycle Cell Cycle Proteins Cell Cycle Regulation Cell Cycle Stage Cell Differentiation process Cell Line Cell Nucleus Cells Clinical Defect Development Disease Erythrocytes Erythroid Erythroid Cells Erythropoiesis Fetal Hemoglobin Fluorescence Foundations G0 Phase G1 Phase GTP-Binding Protein alpha Subunits, Gs Genes Genetic Hematopoietic stem cells Hemoglobin Hemoglobinopathies Human In Vitro Knock-out Knowledge Lead Mendelian disorder Messenger RNA Methods Mitosis Organ Oxygen Pathogenicity Patients Pharmacology Phase Phosphorylation Population Process Production Proteins Publishing Regulation Research Role Screening Result Sickle Cell Anemia Speed System Testing Therapeutic Tissues Transcription Initiation Site Ubiquitination Validation Work base beta Globin beta Thalassemia career deep sequencing erythroid differentiation experience experimental study gamma Globin genome-wide inhibitor novel novel therapeutic intervention novel therapeutics polymerization promoter skills

项目摘要

ABSTRACT Oxygen delivery to the body’s tissues and organs is dependent on the qualitative and quantitative features of hemoglobin, a tetrameric protein made up of two α- and two β-like subunits. β- hemoglobinopathies are the most common monogenic disorders worldwide, and are defined based on whether patients have quantitative (β-thalassemia) or qualitative (Sickle Cell Disease (SCD)) defects in β- globin synthesis. Unfortunately, there are few treatment options for β-hemoglobinopathies. However, it has been shown that an alternative β-like subunit, γ-globin, has the ability to compensate for the β-globin defect in SCD and β-thalassemia. To date, few potential activators of γ-globin expression have been discovered. Additionally, a recent study showed that steric hindrance at the γ-globin promoter (~150bp upstream of the transcription start site) led to a decrease in γ-globin expression- implying the presence of a γ-globin activator-binding region. Consistent with these findings, I have performed a pooled genome- wide CRISPR activation screen that identified several novel candidate genes that may activate γ-globin expression. In this proposal, I aim to validate these candidate γ-globin activators that I uncovered in my screen and perform studies to determine the mechanism by which these candidate genes increase γ- globin expression. Additionally, in my recent work I have found that a high percentage of slow cycling human erythroid cells express γ-globin (termed F-cells) compared to erythroid cells with normal cycling speeds. In this proposal, I also aim to dissect the impact of cell cycle speed regulation on γ-globin expression. From this work I expect to uncover critical regulators of γ-globin. These newfound regulators may lead to the development of novel therapeutics for β-hemoglobinopathies. Importantly, this proposal will allow me to develop the skills, knowledge, and experience for a successful career in academic research.

摘要