03/08/2022
By Sokny Long
The Francis College of Engineering, Department of Chemical Engineering, invites you to attend a doctoral dissertation defense by William Stuart on “Inhibition of Polycomb Repressive Complex 2 as a Novel Mechanism for Fetal Hemoglobin Induction in Sickle Cell Disease.”
Ph.D. Candidate: William Stuart
Defense Date: Monday, March 21, 2022
Time: 10 a.m. to noon EST
Location: This will be in-person defense (UCC-490), and a virtual option via Zoom will be provided. Those interested in attending should contact the student, bstuart@fulcrumtx.com, and committee advisor, seongkyu_yoon@uml.edu, at least 24 hours prior to the defense to request access to the meeting.
Committee Chair (Advisor): Seongkyu Yoon, Professor, Chemical Engineering, UMass Lowell
Committee Members:
- Peter Gaines, Professor, Biological Sciences, UMass Lowell
- Mark Carlson, Director of Program Management at Nimbus Therapeutics
- Gulden Camci-Unal, Assistant Professor, Chemical Engineering, UMass Lowell
- Mahdi Garelnabi, Associate Professor, Biomedical Sciences, UMass Lowell
- Chiara Ghezzi, Assistant Professor, Biomedical Engineering, UMass Lowell
Brief Abstract:
Sickle Cell Disease (SCD) is caused by a single nucleotide mutation in the hemoglobin β (HBβ) gene that results in a dysfunctional adult hemoglobin protein (HbA) that is the root cause of the increased morbidity and mortality associated with this disease. Individuals with SCD who harbor additional genetic alterations that maintain elevated fetal hemoglobin (HbF) expression during adulthood demonstrate greatly improved disease prognosis and at HbF amounts sufficient to restore normal hemoglobin functions can present as asymptomatic. Elucidating the regulatory networks that control HbF expression is critical to the discovery of new therapies for SCD. BCL11A is a master regulator that acts as a developmental switch and suppresses fetal hemoglobin gene (HBG) expression in adults. Here, it is shown that Polycomb Repressive Complex 2 (PRC2) regulates BCL11A expression in erythroid progenitor cells, and thus is a putative upstream regulator of HBG gene expression. Data indicates negative modulation of PRC2 activity via multiple different pharmacologic or genetic knockdown approaches results in decreased expression of BCL11A and concomitant and robust increases in both HBG mRNA and HbF protein across in vitro and in vivo models of SCD. These novel findings further elucidate the regulatory network that underlies fetal hemoglobin gene expression and has important implications for the use of inhibitors of PRC2 as potential therapies for SCD.
All interested students and faculty members are invited to attend the online defense via remote access.