权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Regulation of hemoglobin production in normal and disease states

正常和疾病状态下血红蛋白产生的调节

基本信息

批准号：
10189076
负责人：
Eugene Khandros
金额：
$ 15.98万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
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：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10189076
关键词：
Address Adult Advisory Committees Attenuated Award Benign Bioinformatics Biological Assay Biology CHD7 gene CRISPR/Cas technology Cell Line Cells Cellular biology Characteristics Chromatin Chromatin Loop Clinical Data Development Development Plans Disease Distal Doctor of Philosophy Enhancers Environment Enzymes Epigenetic Process Erythroblasts Erythrocytes Erythroid Erythroid Cells Erythropoiesis Exhibits Fetal Hemoglobin Fluorescent in Situ Hybridization Funding Future Gene Expression Regulation Genes Genetic Genetic Screening Genetic Transcription Genetic Variation Globin Goals Hematology Hemoglobin Hemoglobinopathies Heterogeneity Human Individual International Kinetics Locus Control Region Maps Mentors Molecular Molecular Biology Nuclear Nucleosomes Pathway interactions Patients Pattern Pediatric Hematologist Pediatric Hospitals Pediatrics Pennsylvania Pharmaceutical Preparations Pharmacology Philadelphia Physicians Physiological Population Positioning Attribute Production Proteome RNA Regulation Research Research Personnel Resources Role SMARCA4 gene SMARCA5 gene Scientist Severities Sickle Cell Anemia Sickle Cell Trait Site Source Stimulus Techniques Therapeutic Training Transcript Transposase Universities Variant base beta Globin beta Thalassemia career career development cell type chromatin remodeling chromosome conformation capture clinically relevant enzyme activity experience experimental study fetal gamma Globin hydroxyurea instructor loss of function novel overexpression pomalidomide promoter research and development response sickling single molecule skills therapeutically effective transcription factor transcriptome

项目摘要

PROJECT SUMMARY / ABSTRACT Reversing the developmental switch from fetal (HbF) to adult hemoglobin is an important therapeutic approach in sickle cell disease (SCD). HbF expression in healthy adults, patients with SCD, or those treated with pharmacologic HbF inducers is distributed heterogeneously in a subset of cells called “F-cells”; increasing the number of F-cells as well as the HbF content in each F-cell are both important for treatment of SCD. I have developed techniques for purification and characterization of primary human F-cells and their comparison to equivalent A-cells, which do not express HbF. My preliminary data show that the two cell types differ primarily in their globin content but not in expression of any known HbF regulators, and that F-cells have increased long- range chromatin contacts between the locus control region (LCR) enhancer and the promoters of the g-globin genes. My preliminary studies and the experiments proposed in this proposal represent the first attempt to characterize F-cells by direct comparison to A-cells. I propose to further characterize F-cells from healthy adults, patients with SCD, and following treatment with three pharmacologic HbF inducers using cutting-edge techniques for studies of transcriptional bursting kinetics, chromatin accessibility and long-range chromatin interactions. In addition, I will explore the function of three chromatin remodeling enzymes identified in a loss of function genetic screen for modulators of HbF expression. My proposed studies will further our understanding of the mechanisms of HbF regulation and heterogeneity of HbF expression in clinically important contexts and will guide the development of more effective therapeutics for sickle cell disease. This proposal describes a five-year training plan for the development of my independent research career as an academic pediatric hematologist physician-scientist studying red cell biology and hemoglobin regulation. I am an Instructor in Pediatrics at the University of Pennsylvania and an attending physician in the Division of Hematology at the Children’s Hospital of Philadelphia (CHOP) with previous PhD training in cell and molecular biology and red blood cell biology. The goals for this award are to develop and refine the essential skills that will be required for a successful career as an independent investigator, including expertise in gene regulation, epigenetics, and bioinformatics. My mentor for this award is Dr. Gerd Blobel, an internationally recognized leader in epigenetics, erythroid gene regulation, and developmental control of hemoglobin switching. I have also enlisted an advisory committee composed of scientists and physician-scientists with complimentary expertise and mentoring experience, and have the full resources of CHOP and the University of Pennsylvania available for the completion of my research and career development goals. Completion of this proposal in a mentored environment will leave me optimally positioned for a career as an independent physician-scientist.

项目摘要/摘要