A Center of Molecular HematologyDescription of Major Goals
Support use of mice and zebrafish as model organisms for hematopoietic development.
Discovery of natural products for induction of fetal hemoglobin for sickle cell diseaseDescription of Major Goals
The goal is to identify new agents for reactivation of fetal hemoglobin (HbF) in adults as treatment for the major beta-hemoglobin disorders, sickle cell disease and beta-thalassemia.
Systems Biology Analysis of Human ErythropoiesisDescription of Major Goals
The major goals of this project are to predict and validate the developmental stage-specific gene regulatory networks in human primary erythroid precursors by integrating genomic and epigenomic data-types; to perturb the gene regulatory networks using molecular and genetic experiments and further integrate such information to refine our network model; and to characterize the role of genetic variants in influencing chromatin state, gene expression, and erythroid traits.
Translational and clinical studies targeting gamma-globin modulationDescription of Major Goals
The goal is to exploit the observation that individuals with propionic acidemia (PA) have enhanced HbF expression, in 3 specific aims, the PI proposes to 1) extend the observation that PA is associated specifically with HbF induction, 2) determine the unique metabolites that may be associated with said induction and 3) examine the effects of candidate metabolites on in vitro erythroid cell cultures. Specific globin gene expression, global gene expression, epigenetic modification of the beta globin locus, and a specific analysis of the effects of these metabolites on HDAC activity are proposed.
Molecular Analysis of Normal and Thalassemic DNADescription of Major Goals
The major goals of this project are to understand how FOG-1 participates in GATA-dependent gene regulation, how GATA-1 functions in gene transcription, and how BCL11A protein controls HbF.
High-resolution and high through-put genome editing to determine minimal repressive sequences within the beta-globin gene clusterDescription of Major Goals
The study will identify a set of CRISPR sgRNAs sufficient to cause substantial disruption of the B-globulin cluster HbF repressive element
Hematopoietic regulators and efficient genome engineeringDescription of Major Goals
The goals of the project are to improve methods for gene engineering of hematopoietic stem cells in mouse and human in order to identify key regulators of blood cell development and self-renewal.
Identification of a development for the treatment of sickle cellDescription of Major Goals
The major goals of this project are to test the feasibility of discovering small molecules with good potential to progress to leads that reduce the activity of BCL11A in repressing γ−globin expression, progress two series through SDS and LD to deliver lead and back-up for candidate selection, and identify one new target within the BCL11A / γ−globin expression pathway for possible entrance into the RDRU drug discover portfolio.
Epigenetic Eradication of Chronic LeukemiaDescription of Major Goals
the major goals of this award are to explore the Ezh2-dependence of CML leukemic stem cells, and to determine that small molecule inhibition of Ezh2 is functionally equivalent to Ezh2 loss.
Developmental Biology of Human Erythropoiesis: PPGDescription of Major Goals
The major goal of this project is to further an understanding of the genetic mechanisms that control the fetal to adult hemoglobin switch.
Human Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood Diseases (7 years)Description of Major Goals
Dr. Orkin is PI of a project focused on the effects of trisomy 21 (Down syndrome) on normal hematopoiesis, leukemia in the setting of Down syndrome, and contributions of trisomy 21 on cardiac development, through the study of trisomy 21 ES and iPS cells.