Completed Grants and Sponsored Research
Sponsoring Organization: University of Colorado-Denver/National Institutes Of Health (NIH)
Sequence analysis of hematologic and hemostasis traits in African Americans - Resubmission
Description of Major GoalsThe goals of this project are to analyze the functional impact of variants, elements, and genes associated with blood cell traits in African Americans. The Bauer lab will design and utilize CRISPR/Cas9 genome editing reagents to investigate the consequence of genetic perturbation of implicated sequences on gene expression and cellular phenotype in hematopoietic cells.
Sponsoring Organization: Doris Duke Charitable Foundation
Small molecule targeted reactivation of HbF for sickle cell disease
Description of Major GoalsThe goal of this project is to transform management of SCD through the development of new drug candidates specifically targeted to interfere with fetal hemoglobin (HbF) silencing. The aims are: Perform comprehensive, fine-resolution functional CRISPR/Cas9 mapping of NuRD complex components; Develop small molecules targeting the bromodomain of ZMYND8; Assess the consequences of ZMYND8 bromodomain domain inhibitors and directed destruction of ZMYND8 protein for HbF induction; and assess the functional consequences of small molecules directed to ZMYND8 for HbF reactivation, and other gene expression and cellular changes, in both wild-type and SCD-patient derived primary CD34 cells.
Sponsoring Organization: Doris Duke Charitable Foundation
High-resolution and High Through-put genome editing to determine minimal repressive sequences within the beta-globin gene cluste
Description of Major GoalsThis research is designed to test the hypothesis that NHEJ-mediated targeted indel production itself would be a favorable therapeutic genome editing strategy for sickle cell disease by disruption of endogenous β-globin gene cluster sequences that repress the expression of fetal hemoglobin.
Sponsoring Organization: Boston Children's Hospital - TRP
Biology studies of hematopoietic stem progenitor cells mobilized by plerixafor from patients with sickle cell disease
Description of Major GoalsThe goal of this research is to study various features of the early blood cells that are collected during the plerixafor trial. We will test whether the plerixafor-mobilized cells are suitable for gene therapy and gene editing.
Sponsoring Organization: American Society of Hematology
Characterization of Enhancers Underlying Human Erythroid Traits
Description of Major GoalsThe goal of this project is to explore genetic determinants of human red blood cell traits that modulate erythroid enhancer elements. The aims are: to compare deletion of trait-associated enhancers to non-trait associated enhancers to investigate the genetic architecture of erythroid traits; and to disrupt trait-associated enhancers to identify variants and genes underlying erythroid traits.
Sponsoring Organization: National Institutes Of Health (NIH)
Identification of sequences and factors required for HbF repression
Description of Major GoalsThe goals of this research are to utilize a high-resolution, high-throughput genome editing approach to identify genetically implicated noncoding sequences (in addition to the GWAS-marked BCL11A enhancer) associated with HbF level and to define trans-acting factors that physically and functionally interact with critical noncoding sequences at BCL11A and HBS1L-MYB.
Sponsoring Organization: Harvard Stem Cell Institute
Targeted Disruption of the BCL11A Erythroid Enhancer in Hematopoietic Stem Cells for Genetic Therapy of the Beta-Hemoglobinopathies
Description of Major GoalsThis research aims to investigate the effects of disrupting the BCL 11 A erythroid enhancer in HSCs and ensure that the modified cells can produce all types of blood cells while also leading to elevated levels of HbF. In addition, we will investigate whether targeting a more specific, enriched HSC population will allow for increased rates of editing and a more effective therapy. The work proposed here will provide important advancements in creating a gene therapy treatment for the 13-hemoglobinopathies as well as improving the use of genome editing technologies in hematopoietic stem cells.
Sponsoring Organization: National Institutes Of Health (NIH)
Research Supplement to Promote Diversity in Health-Related Research Associated with R03DK109232 Identification of sequences and factors required for HbF repression
Description of Major GoalsThe goal of this proposal is to identify mechanisms that regulate HbF level and could serve as rational targets for efforts to re-induce HbF for the β-hemoglobin disorders.
Sponsoring Organization: Cooley's Anemia Foundation, Inc.
Genome Editing of Beta-Globin Gene Cluster Repressive Elements for Beta-Thalassemia
Description of Major GoalsIn this proposal, we will identify minimal sequences at the β-globin gene cluster necessary for BCL11A to repress γ-globin in β-thalassemia erythroid cells; and compare methodologies for safely and effectively performing genome editing of these repressive sequences in primary human β-thalassemia HSCs.
Sponsoring Organization: National Institute Diab & Digest & Kid Diseases (NIDDKD)
Epigenetic regulation of BCL11A in hemoglobin switching
Description of Major GoalsThe goals of this research are to discover molecular mechanisms underpinning hemoglobin switching.
Specific aims include: to investigate mechanisms of BCL11A transcriptional regulation promoting the fetal-to-adult developmental transition; and to functionally evaluate regulatory elements at the BCL11A locus.
Sponsoring Organization: Harvard Medical School
Identification of NuRD subunit domain(s) necessary for Y-globin silencing by functional CRISPR-Cas9 mutagenesis scanning
Description of Major GoalsThe goal of this project is to explore whether a specific domain(s) of NuRD (Nucleosome Remodeling Deacetylase) subunits is necessary for γ-globin silencing and serves as a potential target for HbF reactivation therapy. The long-term goal of this project is to develop a compound(s) that induces HbF by targeting the epigenetic complex regulating globin switching.
Sponsoring Organization: Doris Duke Charitable Foundation
Molecular identification of Psickle in reticulocytes generated from HUDEP-2 cells gene-edited to express Hemoglobin SS in the absence of HbF
Description of Major GoalsMolecular identification of Psickle in reticulocytes generated from HUDEP-2 cells gene-edited to express HbS. This project is designed to enable production of a human cellular model of HbS expression using gene editing and then initial characterization of Psickle activity in HbA and HbS expressing erythroid cells.
Sponsoring Organization: COOLEY'S ANEMIA FOUNDATION, INC
Genome Editing of Beta-Globin Gene Cluster Repressive Elements for Beta-Thalassemia
Description of Major GoalsSpecific Aim 1. Utilize a custom pooled CRISPR guide RNA library to perform high-resolution mutagenesis to determine minimal non-coding sequences at the B-globin gene cluster necessary for HbF repression.
Specific Aim 2. Determine efficiency and specificity of genome editing human HSOCs by measuring rate of on-and off-target editing and impact on HbF level and henatopolesis.