Student Presentation -- Lucas Bennink
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Ph.D. Research Proposal, Monday September 18, 2017 -- Engineering and Characterizing Next-Generation Collagen Hybridizing Peptides for Theranostic Applications

3420 HSEB, 1:15 pm

Speaker: Lucas Bennink. Advisor: Dr. Michael Yu


Abstract:

Collagen is a major component of the extracellular matrix (ECM) acting as a scaffold for cells and is involved with cell differentiation, proliferation and signaling cascades. Due to its role in the ECM, collagen is the most abundant protein in mammals and is found ubiquitously throughout the body, including bones, organs, skin, and blood vessels. In natural tissue homeostasis, collagen synthesis and degradation is delicately controlled as collagen turnover is required for growth and upkeep, but excessive collagen degradation is often associated with numerous pathologic diseases such as cancer, fibrosis, and arthritis. These denatured collagen fragments offer a unique opportunity for targeted therapeutics, as the ability to target excessive collagen remodeling may offer insight into the disease state and its medical intervention.

Collagen hybridizing peptides (CHPs) can target degraded or denatured collagen, from multiple collagen types, with high specificity and have negligible affinity to intact collagen. The design of CHPs is based on the collagen triple-helix, a supersecondary structure which follows a glycine-Xaa-Yaa motif with a high content of proline and hydroxyproline in the Xaa and Yaa positions respectively. Although we have previously identified and explored potential therapeutic applications of CHPs, we have not yet examined their enzymatic stability or their pharmacokinetic/pharmacodynamic (PK/PD) profiles. Furthermore, current first-generation CHP designs have the potential to self-trimerize rendering them unable to hybridize with denatured collagen. This is a major drawback for targeted therapeutics and poses a significant limitation when determining the PK/PD properties of the CHPs.

The overall goal of the proposed work is to overcome current CHP drawbacks, optimize CHP design, and demonstrate the utility of next-generation CHPs for use in theranostic applications. Since the new design may depend on a particular application, we will focus on targeting degraded collagens associated with bone remodeling, and bone diseases while engineering and optimizing CHPs for in vivo use. In order to develop next-generation CHPs for theranostic applications we have outlined three aims: (i) we will determine the degradation profile of multiple CHP derivatives, (ii) design the next generation of CHPs that resists self-trimerization, and (iii) establish their pharmacokinetic and biodistribution profiles.