Research Interests
Our research group includes two teams: One team studies the role of
phospholipase A2 (PLA2) in inflammtory/allergic processes, and their control by
PLA2 inhibition. The other team, headed by Dr. Gregory Barshtein, studies the
role of red blood cell (RBC) flow properties in cardiovascular and inflammatory
conditions.
Role of
phospholipase A2 in inflammatory/allergic processes: Phospholipase A2
(PLA2), which hydrolyzes cell membrane phospholipids (PL), is a super family of
enzymes that consists of two main kinds: the secreted (sPLA2) and the
intracellular (cPLA2and iPLA2) enzymes. By hydrolyzing cell membrane PL, PLA2
initiates the production of numerous metabolites that mediate diverse
pathological states, particularly those related to inflammatory processes. These
includes mainly lyso-phospholipids (LysoPL and PAF), as well as arachidonic
acid, which is metabolized by the cyclooxygenase (COX) pathways into
prostaglandins or by the lipoxygenase (LOX) pathways into leukotrienes - many of
them involved in the development of numerous pathological conditions, especially
in inflammation-related processes. PLA2 enzymes, sPLA2 in particular, are also
linked to cell signaling and production of inflammatory cytokines, apart from
their lipolytic activity. In inducing inflammatory processes, the PLA2 enzymes
may act independently, in synergism, or in antagonism. To differentiate between
the contributions of the PLA2 iso-enzymes, we have designed and synthesized a
prototype of cell-impermeable extracellular sPLA2 inhibitors (ExPLIs), which
control PL hydrolysis at the cell membrane without directly affecting
intracellular activities. Using the ExPLIs, we have studied the involvement of
PLA2s in diverse inflammatory/allergic conditions, in cell cultures and animal
models (see Publications). The interrelationship and cross-talk between the PLA2
iso-enzymes is the focus of our current research.
Role of red blood cell (RBC) flow properties
in cardiovascular and inflammatory conditions: Red blood cells (RBC)
have special properties that are key determinants in blood flow and
hemodynamics: These are their aggregability (tendency to form multi-cellular
self aggregates), deformability, flexibility (ability to change their shape in
order to pass through blood capillaries), and potential adherence to blood
vessel wall endothelium. Normally, RBC are singly dispersed, sufficiently
deformable, and their adherence to vessel wall is negligible. However, under
pathological conditions, mainly cardiovascular, inflammatory and oxidative
stress states, RBC aggregability, rigidity and adherence are enhanced, resulting
in flow hindrance and irregular flow patterns, leading to reduced tissue
perfusion and infarct. To comprehensively investigate the role of RBC
hemodynamics in the pathophysiology of circulatory disorders, we have designed
and constructed a unique computerized cell flow properties analyzer (CFA), which
enables the direct visualization and monitoring of the dynamic organization of
RBC in a narrow-gap flow chamber, under controllable flow conditions resembling
those in a microvessel. The CFA, which is a most advanced and sophisticated
imaging system for in-vitro monitoring of RBC hemodynamics, provides an array of
parameters, some newly defined, for comprehensive characterization on RBC flow
properties and their alteration in pathological conditions. The CFA has been
employed in a number of laboratories for studying the involvement of RBC flow
properties in the pathophysiology of cardio-vascular and inflammatory
conditions, as well as for studying effects of blood banking procedures on the
hemodynamic behavior of blood for transfusion therapy. Our current research
focuses on elucidating biochemical and physical factors in RBC that are
responsible for the alteration of their flow properties in pathological
conditions and during blood banking procedures.
