While the molecular
defect that cause sickle cell disease has well been established, the cause of
vaso-occlusive crisis remains elusive and largely debated upon. Majority of
studies have linked the painful episodes to polymerization of sickle hemoglobin
following its deoxygenation. The variability of the disease symptoms among
patients, compounds efforts for a holistic therapy. Hydroxyurea, a stimulator
of Hb F induction and a widely used treatment, has ameliorated the complication
of SCD but it is only effective in 50% of the patients. Expression of Hb F
lowers the content of Hb S in blood and hence reduces oxidative stress caused
by Hb S denaturation. Sickle cell disease severity depends on several factors.
Most importantly, the ability of red cell to sickle dominates all other
determinants. While deoxygenation of sickle hemoglobin may be inevitable, the
duration with which the red cell remains in the deoxygenated state can be
manipulated. Deoxygenation is a transient process that when compared to the
time taken to develop the long filaments of deoxyhemoglobin to causes severe
sickling, the red cell would have been cycled back to the lungs and
re-oxygenated to restore the healthy conditions of the cell. In fact, if sickle
cells would flow as fast as healthy erythrocytes, the detrimental impacts of
sickling such as vaso-occlusive crisis, would not be a concern for this
disease. Unfortunately, the unstable sickle hemoglobin undergoes denaturation
through auto-oxidation, which imposes oxidative stress to the cells. The
oxidative stress inhibits erythrocytes tyrosine phosphatases, a course which
subsequently impair their constitutive action against the tyrosine kinases. In
the end, a net tyrosine phosphorylation state in the red cell membrane
proteins, most notably the transmembrane protein band 3, succeeds. Band 3
tyrosine phosphorylation abrogates the protein’s interaction with ankyrin and
spectrin-actin cytoskeleton, hence the cytoskeleton loses its major anchorage
to the membrane thus engendering membrane destabilization. A destabilized
erythrocyte sheds membrane fragments in form of microvesicles/microparticles
and discharges free hemoglobin into the extra cellular matrix. In consequence,
the microparticles power initiation of coagulation cascade through activation of
thrombin, while free Hb inflicts inflammation, scavenges nitric oxide which is
necessary for vasodilation and induces further oxidative stress within the
microvasculature, and activates expression of adhesion receptors on the
endothelium. Taken together, these events culminate in entrapment of red cells
(not naming leucocytes and platelets) in the microvasculature, blockade of
blood vessels and further damage of erythrocytes through prolonged deoxygenated
state thus terminating in tissue injury, strokes, and organ damage, amid
vaso-occlusive episodes which always require hospitalization and extensive
medical care for survival. Band 3 tyrosine phosphorylation and membrane
weakening is not unique just to SCD, but also a druggable target for malaria.
Malaria, a disease that is touted as the evolutionary cause of sickle cell
disease, surprisingly thrives through the same mechanism. Briefly, malaria
parasite consumes hemoglobin for its DNA synthesis, and in the process generate
reactive oxygen species from denatured hemoglobin that feeds into the oxidative
stress which triggers band 3 tyrosine phosphorylation. In this case however, a
destabilized membrane offers perfect conditions for merozoites’ (malaria
daughter parasites) egress/exit out of the cell to begin infecting other red
cells. Ultimately, the ensuing anemia and organ dysfunction leads to patient’s
death. Treatment of diseased cells with imatinib and other Syk inhibitors
effectively reversed membrane weakening. A stabilized membrane not only
survives longer in circulation to alleviate SCD symptoms but also traps and
starves malaria parasite leading to termination of the parasitic infection.
With band 3 tyrosine phosphorylation at center stage, this dissertation
explores the above events in an effort to unveil a novel therapy for sickle
cell and malaria diseases. First, the therapeutic strategy regarding SCD is
discussed in detail beginning with non-transfused patients and ending in
additional mechanistic study on inactivation of the principal erythrocyte’s protein
tyrosine phosphatase 1 B, PTP1B. The dissertation then provides an initial
proof of concept on efficacy of imatinib in treatment of malaria as a
monotherapy and its efficacy when used in a triple combination therapy with the
standard of care treatment. Finally, I outline an alternative possible
mechanism of action of quinine against malaria.
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/14502330 |
| Date | 29 April 2021 |
| Creators | Panae Noomuna (10716546) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/INHIBITION_OF_ERYTHROCYTE_BAND_3_TYROSINE_PHOSPHORYLATION_CHARACTERIZATION_OF_A_NOVEL_THERAPY_FOR_SICKLE_CELL_DISEASE_AND_MALARIA/14502330 |
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