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(Unpublished)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