Andrius Kazlauskas

Signaling that governs angiogenesis

Many of the signaling events that contribute to angiogenesis have been identified, and this body of information provides the foundation to investigate how each signaling enzyme contributes to various phases of the angiogenic program.  We are studying the following 4 projects:
1. Signaling events that are required for vessel formation and stability.  
2.  Apoptosis-independent pathways that govern regression of vessels.  
3.  The mechanism by which pericytes stabilize vessels.
4.  Diabetes-induced deregulation of angiogenesis.  

Phases of the Angiogenic Program 

The role of PDGF in PVR

Proliferative vitreoretinopathy (PVR) is a complication that develops in 5-10% of the patients undergoing surgery to attach a detached retina.  The current therapeutic approaches for PVR are primarily surgical, and have only limited success.  Our overall goal is to develop complementary approaches to treat these patients.  Our strategy is to define the molecular mediators of PVR in an animal model of the disease.  To this end we have been focusing on the growth factors that are present in the vitreous and likely to promoting proliferation and survival of cells that organize the epiretinal membrane that develops in PVR.  These studies have lead to a number of surprises, including the observation that growth factors outside of the platelet-derived growth factor (PDGF) family activate the PDGF receptor and promote PVR.  

How growth factors drive cell cycle progression

The traditional view of how growth factors promote entry of quiescent cells into the cell cycle is that cells first encounter a competence factor, which makes them capable of exiting G0.  Subsequent exposure to a second type of growth factor (a progression factor) drives cells out of G0, through G1 and past the restriction point, whereupon cells are committed to one round of the cell cycle.  

Since the introduction of these concepts approximately 35 years ago, the major advances in this field have been to molecularly define the components of the cell cycle program and the restriction point.  We now know that the restriction point consists of inactivation of Rb, which results from its phosphorylation by cyclin dependent kinases that are activated in response to growth factors during the second half of G1.  Despite these advances, major unanswered questions persist.  For instance, how signaling events that are triggered by growth factors at the G0/G1 transition license cells to engage the cell cycle program in the second half of G1 is a mystery.  

Recent work indicates there are two segments of the G1 phase of the cell cycle. The first is a priming phase, during which cells prepare to engage the cell cycle program, and the second segment is a completion phase, during which the cell cycle program is active.  Our goal is to molecularly define the priming phase of G1 phase.  Our working hypothesis is that priming cells induces the expression of proteins that license cells to engage the cell cycle program in the second half of G1.  Our goal is to molecularly define the priming phase of G1 phase.  Our working hypothesis is that priming cells induces the expression of proteins that license cells to engage the cell cycle program in the second half of G1.