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Defining the mechanisms of hemoglobin switching and genotoxicities associated with its manipulation

Award Number: K01DK132453
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/21/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Defining the mechanisms of hemoglobin switching and genotoxicities associated with its manipulation - Project Summary Induction of fetal hemoglobin (HbF, α2γ2) by genome editing is a promising therapeutic strategy for β- hemoglobinopathies. The focus of my work is to better understand the developmental regulation of γ-globin expression and investigate the genotoxicities associated with genome editing of CD34+ hematopoietic stem and progenitor cells (HSPCs) to induce HbF therapeutically. My recent studies have utilized functional genomics to identify key DNA regulatory motifs in the γ-globin promoter that are essential for gene expression following therapeutic genome editing or in non-deletional hereditary persistence of fetal hemoglobin (HPFH). HPFH is a benign, genetic condition in which point mutations or small deletions cause sustained γ-globin expression in adult red blood cells. However, the regulation of γ-globin expression normally, and in some forms of HPFH, remain incompletely defined. In parallel related studies, I have shown in HSPCs that Cas9-induced double-stranded DNA breaks (DSBs) resulting from therapeutic genome editing to induce HbF can cause chromosome segregation errors during cell division, leading to micronucleus formation and copy number abnormalities of the telomeric chromosomal segment. Most cells with these abnormalities should be eliminated by endogenous DNA damage surveillance mechanisms. However, micronuclei resulting from DSBs can also lead to stable chromosomal rearrangements, chromothripsis, and malignant transformation. Hence, it is important to determine whether these abnormalities persist after editing of HSPCs. For this K01 proposal, I will continue my two separate but related lines of investigation to better understand the regulation of γ-globin transcription and the genotoxicities associated with therapeutic genome editing to induce HbF. Specifically, I will map a newly discovered regulatory element in the γ-globin locus and define the epigenetic changes and transcription factors important for deletional HPFH, which is caused by kilobase-scale deletions of the extended β-globin locus, using population and single- cell genomics (Aim 1). In parallel, I will investigate whether micronuclei and chromosomal abnormalities persist after DSBs in HSPCs. Through whole genome sequencing, live-, and fixed-cell immunofluorescence, I will study Cas9-induced chromosome instability, structural variations, and DNA damage sensing pathways in HSPCs in vitro with the long-term goal of studying the persistence of chromosomal abnormalities in vivo (Aim 2). The successful completion of this K01 career development award will form the foundation for my long-term career goal of establishing an independent research program that investigates the mechanisms of gene regulation and DNA damage sensing to leverage this information for improved genetic therapies. The proposed research and training plans within the academic environment will ensure a successful path for independence.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $158,220 )
2026	2026	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	12/3/2025	NON-COMPETING CONTINUATION	$158,220
														Subtotal = $158,220

Issue Date FY: 2025 ( Subtotal = $158,220 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	3/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$129,319
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	4	9/5/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$28,901
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	3/31/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	3/4/2025	NON-COMPETING CONTINUATION	$0
2025	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	4/10/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $158,220

Issue Date FY: 2024 ( Subtotal = $129,319 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/4/2024	NON-COMPETING CONTINUATION	$129,319
														Subtotal = $129,319

Issue Date FY: 2023 ( Subtotal = $183,318 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/27/2023	SUPPLEMENT FOR EXPANSION	$53,999
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/26/2023	NON-COMPETING CONTINUATION	$129,319
														Subtotal = $183,318

Issue Date FY: 2022 ( Subtotal = $130,819 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/24/2022	NEW	$130,819
														Subtotal = $130,819

Grand Total All Awards = $759,896

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Defining the mechanisms of hemoglobin switching and genotoxicities associated with its manipulation

Award Number: K01DK132453

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/21/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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