[CCoE Notice] Dissertation Defense: A Free Heme Perspective to Sickle Hemoglobin Polymerization

[Grayson, Audrey A]

Anupam Aich- PhD Defense Announcement


DATE: Thursday, April 16, 2015

TIME: 10:00 a.m.

PLACE: Mechanical Engineering Conference Room (Small)

DISSERTATION CHAIR: Dr. Peter Vekilov
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TITLE:
A Free Heme Perspective to Sickle Hemoglobin Polymerization

Abstract
Sickle cell hemoglobin (HbS) polymerization is considered to be the primary pathogenic event in the sickle cell anemia. Many cellular and molecular factors have been identified so far as contributor towards the polymerization event. The free heme, prosthetic group of hemoglobin, is one such small molecule which has been previously shown to enhance the polymerization by orders of magnitude and removal of free heme from the supersaturated HbS solution stops the polymerization completely.
In the present study we set out to investigate the free heme concentration in normal adult and sickle cell erythrocytes. We used an enzymatic chemiluminescence assay for the determination of free heme in erythrocytes. The average free heme concentration in sickle cell patients is 44±9 mM, in sickle trait individuals—33±4 mM, and in healthy adults—20±2 mM. We also found that heme release is autocatalytic and results from spectral determination of methemoglobin percentages over time indicate towards well known higher susceptibility of sickle hemoglobin to autoxidation as mechanism for the release. We propose a link between physiological oxidative stress and autocatalytic heme release through imbalance in the reductase homeostasis in the erythrocytes. Inherent kinetic instability of autocatalytic processes may contribute to the known variability of the patients. Looking at the previous polymerization experiments and combining the current results we propose free heme and its release factors to be new targets for therapeutic and drug discovery for sickle cell anemia disease. We also provide a preliminary design of a cell separation device based on deformability induced margination flow for fractionating sickled and unsickled cells in 100% deoxygenated condition. If completed in future, this device promises a biomarker detection platform for sickle cell disease.
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