Research

My own research program is focused on the mechanisms governing the pathological and adaptive vasculature development and neoangiogenesis in adult organisms. We incorporate state-of-the-art animal models of human diseases including various models of ischemic injury, myocardial infarction, thrombosis and angiogenesis. At the molecular level, we have focused on the extracellular matrix, receptors for matrix components (integrins), angiogenic growth factors (VEGF-Vascular Endothelial Growth Factor) and their receptors (VEGFRs).

In our previous studies, we uncovered novel communication pathways between VEGF, its receptors (VEGFR2) and cellular receptors for extracellular matrix (integrins). We have demonstrated that the complex between integrins and VEGFR2 is a key regulator of pathological angiogenesis in vitro and in vivo (Byzova et al, Mol Cell; Mahabaleshwar et al, J Exp Med; Mahabaleshwar et al, Circ Res). We have also determined structural requirements for their physical association and designed compounds which selectively disrupt the complex and show high anti-angiogenic activity in vivo. We found that the PI3K/Akt pathway plays a key role in integrin regulation on different cell types and therefore influences pathologies extending from thrombosis to tumor progression (Chen et al, Nat Med; Chen et al, Blood). We uncovered a novel function of Akt kinase in vascular biology and identified several unique downstream mechanisms by which it controls angiogenesis, vascular maturation, integrity, and matrix composition. We demonstrated that a VEGF-dependent autocrine loop on many tumor cell types maintains cell-surface integrins in a constitutively activated state and therefore is responsible for the high invasive phenotype of cancer cells. Using in vivo models, we demonstrated that not the presence but, importantly, the activation of integrins is responsible for tumor growth and tumor-induced remodeling of host tissues including angiogenesis and bone remodeling. Thus, with integrins, VEGF, and Akt as key molecular players, we have defined a mechanism for regulation of pathological angiogenesis.

Recently, my lab identified a molecular mechanism for a previously unrecognized human disease that presented with severe bleeding, frequent infections and osteopetrosis. Mechanistically, these symptoms arose from an inability to activate the integrins expressed on their hematopoietic cells (Malinin et al, Nat Med).  The genetic basis for this disease was traced to a single point mutation in the coding region of the gene that encoded the cytoskeletal protein, Kindlin-3. This finding established an essential role of Kindlin-3 in activation of three families of integrins in humans. We continue our studies on the role of Kindlin-3 in integrin activation. Other (still unpublished) studies in the lab are focused on the role of platelets and bone marrow derived cells in angiogenesis with a focus on integrins. Another part of my program concerns stem cells in angiogenesis and cancer progression.