The candidate has a multidisciplinary background in chemistry, biochemistry and engineering. These fields will be combined to develop stable, high affinity integrin binding proteins for mediating cell adhesion and angiogenesis in cancer. The candidate will spend a year in a mentored position in the laboratories of William F. DeGrade and Joel S. Bennett at the University of Pennsylvania School of Medicine. During this period, the applicant will develop skills in peptide and protein design, and organic synthesis while in the DeGrade lab. Experience in integrin receptor function and biological assays will be gained in the Bennett lab. This period will be important in establishing the groundwork for the unmentored portion of the award. The remainder of the award will be spent in an independent, preferrably tenure-track, academic position, where the applicant will build upon this additional expertise to develop biomolecules for cancer therapeutics and tumor imaging applications. The University of Pennsylvania School of Medicine has a strong commitment to research in health and human disease, and several of its faculty are conducting integrin and/or cancer related research. The mentors chosen by the applicant have well-established, productive collaborations in studying the structure and function of integrin proteins. In addition, Prof. DeGrade has much expertise in development of integrin-specific mimics through rational design and combinatorial library panning in collaboration with DuPont. Integrin-specific peptide mimics and antibodies have shown much therapeutic promise in the inhibition of angiogenesis and metastases in tumors, but can benefit greatly from stability and affinity maturation. The mentored period of the award will involve incorporation of integrin-specific peptide motifs into constrained molecular scaffolds to increase stability and binding affinity. These scaffolds will provide the framework for a portion of the unmentored period of the award, where integrin binding proteins will be engineered to even higher affinity using directed molecular evolution by yeast surface display. In addition, the mentored period of the award will focus on the design and synthesis of a series of novel peptide-based crosslinking reagents. These compounds will be used for creating multivalent integrin-specific peptides and proteins for high avidity binding and enhanced antagonism. In the unmentored period of the application, a nonimmune human library of scFv antibody fragments displayed on the surface of yeast will be used to isolate a panel of integrin-specific binders. These antibodies will be characterized for their ability to inhibit RGD-mediated binding and cell adhesion. Promising antibodies will be engineered to ultra high affinity and stability using yeast surface display to develop potent integrin antagonists.
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