The Role of G13 in Platelet Physiology
Abstract: In the early
1900's the leading cause of death in the United States was due to infectious diseases.
The average expected lifespan was approximately 50 years, and therefore chronic diseases
were not as impactful on the general population. As lifespan increased throughout the
century, the critical role of cardiovascular disease and chronic hypertension was
revealed as a silent burden ... read moreplaguing the country and the world. Currently, CVD is a
leading global cause of death, particularly in developing nations with inadequate access
to medical care and treatment. Some contributors to CVD are familial
hypercholesterolemia, hypertension, diabetes, smoking, and a high cholesterol diet. Due
to its prevalence and complex etiology, it is critical to identify new treatment options
that can prevent and treat patients at risk for major cardiovascular events.
Cardiovascular disease begins with the formation of fatty streaks along the arteries,
which signify the accumulation of cholesterol beneath the vessel wall. The vessel wall
is composed of a monolayer of tightly packed cells known as endothelial cells (ECs). A
major role of ECs is to maintain the structural integrity of the vessel wall to prevent
hemorrhaging, while simultaneously creating a non-adhesive environment so blood cells
can easily pass through. As CVD progresses, the fatty streak begins to irreversibly
disrupt the endothelial cell barrier as well as induce endothelial cells to display
receptors that make them "sticky." Subsequently, platelets, white blood cells, and
erythrocytes begin adhering to these sites, contributing to a highly inflammatory
environment. Over time, a series of remodeling events progress resulting in fibrous
lesion formation known as the atherosclerotic plaque. These plaques tend to be unstable
and their rupture can be triggered by a number of stressful events. Immediately after
the plaque rupture, platelets adhere to the injured site and accumulate into a
relatively large thrombus. In severe cases, these thrombi can occlude the vasculature
(ischemia) or detach and possibly occlude the vasculature of the heart (myocardial
infarction/MI) or the brain (stroke). Therefore, there is great interest in developing
anti-platelet drugs as potential therapies against MI and Stroke. Our laboratory has a
long-term interest in investigating the molecular mechanisms of thrombus formation.
Platelets must bind to soluble 'bridging' molecules in the blood that can link two or
more platelets together. This process is facilitated by a series of signaling events
within platelets that culminate in the activation of receptors on the platelet surface.
These signaling events are accomplished through the mobilization of calcium, which
activates a family of proteins known as G proteins. Activation of G proteins in
platelets leads to a multitude of signaling processes that are indispensable for
platelet functionality. We, and our collaborators, have recently developed a novel small
peptide-based therapeutic approach against platelet Gα13 that can dramatically
diminish thrombus formation in vivo. The treatment is based on a highly conserved Switch
Region 2 sequence of Gα13 that plays a crucial role in platelet activation. These
findings may lead to new anti-thrombotic drugs as potential prophylactic treatment for
patients at risk for major cardiovascular
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisors: Athar Chishti, and Michael Forgac.
Committee: Michael Forgac, Andrew Bohm, and Laura Liscum.
Keywords: Biochemistry, and Biology.read less