Work in the lab continues to be focused on revealing key insights into many fundamentally important processes that govern: (i) cell movements required for cell division, (ii) the folding of the embryo, (iii) differentiation of the body’s organ systems as well as (iv) the remodeling of tissues during disease processes. Because of our basic interests in understanding the molecular and cellular mechanisms controlling cell shape and motility, we continue to find ourselves at the intersection of cell and molecular biology, developmental biology and regenerative medicine. We seek to understand the molecular mechanisms underlying the migratory and proliferative cellular responses to injury and wound healing, the remodeling of the vasculature during physiologic and pathologic angiogenesis, and the cytoskeletal-specific adaptive responses during host-pathogen interactions. Our basic studies continue to be translated into several biomedically-relevant arenas, including the innovative design of bioengineered tissue constructs for the promotion of chronic wound healing and regenerative medicine, the development of strategies aimed inhibiting pathologic angiogenesis or the creation of non-antibiotics based therapies capable of abrogating microbial pathogenesis. There are currently three tracks of related research that are ongoing, including:

1. Fundamental insights into cytoskeletal remodeling and cell migration.

Localization of β actin is confined to regions of advancing cytoplasm. Note that rhodamine anti-β actin IgG is exclusively localized at the leading edge of crawling cells in response to injury. (Nuclei: Blue; Stress fibers: Green)

Based on prior work and current analyses that are ongoing in the lab, we postulate that the regulation of isoactin-based cell motility is precisely regulated by a repertoire of actin-associating proteins that collectively function to control and signal through the actin network to influence cell shape and motility. We currently take advantage of vascular and epithelial cell model systems, as well use molecular genetic approaches that implement adenoviral-mediated gene delivery as well as transgenic animals to test whether our hypotheses are valid. In turn, fundamental insights derived from these experiments are helping us to develop innovative strategies capable of enhancing or abrogating cell motility, during wound healing or diabetic retinopathy or tumor progession, respectively.

2. Molecular control of microvascular morphogenesis: insights into pathologic angiogenesis.

Our work in the angiogenesis of wound healing and pathologic angiogenesis is focused around our devotion to understanding the molecular signaling cascades that control microvascular remodeling during diabetes and chronic wound healing. To these ends, we have developed several in vitro and animal model systems to enable our dissection of mechanisms, interrogation of specific hypotheses as well as perform high throughput screenings of relevant libraries: all efforts focused on developing innovative strategies capable of accelerating the angiogenesis of wound healing or inhibiting the unwanted vascular proliferative lesions present in the posterior pole of the human eye, which are presented during diabetic retinopathy or age-related macular degeneration. In turn, this work has also permitted our recent development of novel therapeutics that promote cell migration and accelerate wound healing as well as helped to foster the production of innovative 3-D wound healing models and therapeutics.

To gain insight into the molecular and cellular mechanisms regulating the cellular responses to injury and wound healing, microvascular remodeling during developmental and disease-associated processes, and the cytoskeletal mediated responses to pathogenic challenge, we are focusing our attention and efforts using several hypothesis-driven and screening-based approaches, taking advantage of many different approaches, including molecular genetics, cell biology, bioengineering, biochemistry, biophysics and imaging technology. Key diseases that we are targeting include chronic wound healing, diabetic retinopathy, age-related macular degeneration, pathogenic bacterial infections, hypertension, tumor angiogenesis and atherosclerosis. Our in vitro and in vivo approaches incorporate quantitative analyses of (1) tissue activation and remodeling, (2) cytoskeletal and matrix-dependent signaling mechanisms and (3) efforts aimed at revealing therapeutic entry points, whether to interfere with unwanted vascular proliferative disorders, or strategies focused on promotion of new blood vessel growth where ischemia-related injury is problematic.

3. Understanding the molecular mechanisms of host-pathogen interactions: signaling through the network of actin effectors.

Recent work has revealed that the novel isoactin-specific signaling complex of proteins discovered in the lab plays a pivotal role in regulating the remodeling of the apical actin network, which is critical for bacterial pathogenesis. By creating mutant stable cell lines, we have begun to characterize the common molecular mechanisms mediating such diverse phenomena as attaching and effacing lesion formation during enteropathogenic bacterial infection and pathologic angiogenesis.