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Role of CYB5R3 in erythropoiesis and sickle cell disease

Chowdhury, Fabliha Ahmed (2024) Role of CYB5R3 in erythropoiesis and sickle cell disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Cytochrome b5 reductase 3 (CYB5R3) is critical for sustaining numerous reduction reactions in pathways that govern cholesterol biosynthesis, heme reduction, drug metabolism and lipid desaturation. Loss-of-function genetic variants in CYB5R3 results in two clinically distinct phenotypes defined as Type I and II congenital methemoglobinemia. Type I is restricted to erythrocytes causing cyanosis, whereas Type II results in severe neurological complications and childhood death. With more than 40 genetic variants identified to date, CYB5R3 T117S stands out with ~50% loss of activity and has an enriched allele frequency in individuals of African ancestry, an ethic group that also bears a high burden of sickle cell disease (SCD). SCD arises from a single point mutation in hemoglobin beta which results in erythrocyte sickling leading to hemolysis, severe anemia, toxic oxidative and inflammatory imbalance, vasculopathy, end-organ damage and early death. In a hemolytic-anemia disorder like SCD, where stress erythropoiesis is induced to constantly replenish lysed erythrocytes, CYB5R3 may be critical for erythropoiesis. Hydroxyurea (HU) is the FDA approved first line therapy for SCD that induces fetal hemoglobin (HbF) to protect against sickling and its downstream effects. However, for unknown reasons, severe interpatient variability in HU-induced effects has been observed. Given the importance of CYB5R3 in redox signaling and hemoglobin iron recycling, we rationalize that CYB5R3 may play a major role in HbF induction pathway and erythropoiesis. This thesis reveals the importance of CYB5R3 activity as a modifier of HU efficacy for treating anemia in SCD patients. Our findings indicate the involvement of CYB5R3 in the erythropoiesis-associated heme biosynthesis pathway which may help to explain the inefficacy of HU to induce HbF and erythrocyte maturation in SCD. Lastly, this research evaluates the effect of a novel electrophilic quinone-nitroalkene hybrid molecule in SCD, that is known to have anti-oxidative and anti-inflammatory effects and induces CYB5R3 activity. Overall, this thesis provides important new insights highlighting the significance of CYB5R3 in erythropoietic pathway and SCD that may enable novel drug development strategies and clinical decision-making for patients with erythropoietic disorders.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Chowdhury, Fabliha Ahmedfac48@pitt.edufac480000-0002-7966-3514
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorStraub, Adamastraub@pitt.eduastraub
Committee ChairShiva, Srutisss43@pitt.edusss43
Committee MemberPagano, Patrickpagano@pitt.edupagano
Committee MemberQiming, Wangqjw1@pitt.eduqjw1
Committee MemberSchopfer, Franciscofjschopfer@katz.pitt.edufjschopfer
Committee MemberEpperly, Michaelepperly@pitt.eduepperly
Date: 14 October 2024
Date Type: Publication
Defense Date: 17 June 2024
Approval Date: 14 October 2024
Submission Date: 19 July 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 150
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: CYB5R3, sickle cell disease, erythropoiesis, hydroxyurea, CP50, hemoglobin
Date Deposited: 14 Oct 2024 15:00
Last Modified: 14 Oct 2024 15:00
URI: http://d-scholarship.pitt.edu/id/eprint/46701

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