This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)
0853705 Leckband
The broad goal of this research is to use engineering approaches to identify fundamental mechanisms and biological design rules that control the assembly and stability of intercellular junctions in tissues. This research focuses on a class of proteins, cadherins, which are essential for the formation and maintainenance of organized tissues. Engineering approaches, including nanomechanics, cell manipulation, and surface chemical modification will address three key aspects of cadherin function that are central to cadherin's role in developmental biology, tissue formation, and bioengineering: specifically, (1) the physical chemical basis of selective cell-to-cell adhesion, (2) molecular mechanism(s) of cadherin activation and affinity modulation by a novel class of activating (and potentially therapeutic) antibodies, and (3) mechanical transduction between cells and the link between cadherin subtype, adhesion biophysics, and cadherin-dependent intracellular signaling.
The intellectual merit of this research lies in the novel discoveries engendered by this multidisciplinary combination of engineering, biophysics, and cell biological approaches. Preliminary studies by this PI already identified unique thermodynamic and kinetic signatures of cadherin-mediated cell-to-cell adhesion. This enabling discovery will further the identification of distinguishing mechanistic features that are postulated to underlie the selective adhesion between cells, affinity regulation, and signal transduction by these essential adhesion proteins. Aim 1 exploits these findings i) to identify mechanisms of cadherin adhesion and ii) to quantify kinetic and thermodynamic parameters that influence selective cell-to-cell adhesion. The transformative power of these investigations lies in their capacity to identify the physical chemical properties of cadherin bonds postulated to direct cell segregation during tissue formation (Aim 1). Related investigations will in turn identify how recently isolated, cadherin-activating antibodies increase (or modulate) cadherin binding affinity (Aim 2). Activating antibodies have tremendous therapeutic potential, and these studies will define general, molecular design rules for biochemical modulators of cadherin adhesion. Finally, Aim 3 extends the PI's preliminary findings that different cadherins elicit distinct intracellular signaling responses that are seemingly independent of the protein bond strengths. This entirely novel result constitutes a major paradigm shift, because in four decades of research, attempts to determine the basis of cadherin-specific cell interactions exclusively focussed on the extracellular domains. Aim 3 exploits this unique discovery, and will break new ground in identifying key biological design rules that regulate tissue (cadherin)-specific cell functions.
The broad impact of this program derives from its direct relevance to bioengineering and human health and from its educational impact through outreach to women and minorities at both the pre-college and undergraduate levels. Cadherins are essential for tissue genesis and they maintain the structural integrity of all solid tissues; consequently, the results of this program will impact several areas of bioengineering and basic cell biology, including, neural development, embryogenesis, cancer, diseases of the intestinal epithelium, vascular leakage diseases, wound healing, tissue regeneration, stem cell differentiation, and tissue engineering. For example, in collaboration with B. Gumbiner at the University of Virginia Medical School, the research team will uniquely determine the mechanism(s) of cadherin affinity modulation by novel, cadherin-activating antibodies, which could potentially treat a wide range of cadherin-related diseases. Investigations of cadherin binding and intracellular signaling will further identify physical and bio-chemical mechanisms that may contribute to cell segregation, tissue patterning, and possibly tissue-specific functions during tissue formation, repair, and regeneration. These investigations will also identify biochemical and biophysical parameters that are required to mimic cell-cell interactions in tissue scaffolds and engineered environments.
Several of the technologies described in this proposal will also be used as vehicles for outreach activities to middle school girls, minority undergraduates, and women and minorities in Chicago area high schools. In partnerships with outreach programs at the University of Illinois, the PI seeks to alter preconceptions of science and scientific careers often held by middle- and high-school students. She will also use some of the research activities described in this proposal to mentor undergraduates participating in summer research projects for underrepresented minorities in science and engineering.
This program will also continue to support the training of students from underrepresented groups in science and engineering. The PI has mentored 16 senior thesis students, approximately 40% of which were women. At the graduate level, the PI mentored 2 female Masters candidates, 9 female PhD candidates, 2 African American PhD candidates, and one Hispanic male PhD student. This program offers timely research opportunities that will continue to attract diverse students and provide quality opportunities in research and engineering from pre-college to graduate educational levels.
