Protein Chaperone Nanoparticles - Abiotic Mimics of Heat Shock Proteins

点击翻译按钮获取中文摘要

This award by the Biomaterials program in the Division of Materials Research is to develop novel, low cost, abiotic, thermally responsive polyacrylamide hydrogel nanoparticles with chaperone-like activity to stabilize proteins at elevated temperatures. The chaperone-like function arises from two 'engineered' properties of the synthetic polymer nanoparticles: 1) an intrinsic antibody-like protein affinity; and 2) a lower critical solution temperature (LCST), which can be used to trap protein at elevated temperatures, preventing its aggregation and denaturation, and release of the protein upon cooling below the LCST without the need for additives and preserving the overall function of the protein in solution. The concept of creating 'smart' synthetic polymer molecular chaperones, where the antibody-like protein affinity of synthetic polymer nanoparticles is utilized to stabilize a target protein by inhibiting denaturation and/or protein-protein aggregation and the resulting loss of activity. The second 'smart' function of the synthetic polymer nanoparticles arises from its thermal response to temperature. The polymer is in a collapsed state at a temperature above its lower critical solution temperature, where it has protein binding affinity. These two unique polymer properties allow engineering the protein binding affinity of the nanoparticle so that it is switched on and off in response to temperature. One application would be a nanoparticle that sequesters and stabilizes a target protein at elevated temperatures, where the protein is vulnerable, but that has little or no affinity for the protein at room temperature so as to not impede the proteins function. A 'smart' material with this property would find applications by protecting proteins from denaturation. It could also help reduce the cost of protein therapeutics and diagnostics, which arise in part due to the retention of efficacy of the drugs during transportation and storage. This proposal will engage graduate students, undergraduates and high school students in an interdisciplinary research program that spans polymer synthesis, materials chemistry, biology and biotechnology. Additionally, the project will provide students with an opportunity to work with industrial collaborators on practical problems, which could have profound impact on the world-wide delivery of health care. Proteins are large biopolymers produced by all living systems. They play an essential role in all biological processes including regulatory processes, the immune system, catalysis of all biochemical reactions among other functions and properties. Despite their complexity, advances in molecular biology and biotechnology have made proteins readily available. These 'engineered' proteins are now produced and used on a large scale for applications that go far beyond their intended biological functions. These applications include therapeutics and diagnostics, and synthesis of value-added chemicals. Proteins, however, have several limitations. They are not stable when taken beyond physiological conditions of temperature and pH. In particular, they are often unstable at conditions above room temperature, and this temperature sensitivity can limit the use of proteins particularly where refrigeration facilities are not easily available. Maintaining protein functions depend on the availability of a network of cold storage facilities, which will provide optimal cold temperatures during transport, storage, and handling. Nature has evolved strategies to protect proteins from elevated temperatures. A class of biomacromolecules collectively referred to as heat shock proteins, 'protect' vulnerable proteins against loss of function at elevated temperatures. This proposed study is in developing simple, low cost synthetic polymers that can mimic the behavior of heat shock proteins. These 'engineered' synthetic polymer nanoparticles are being designed to 'protect' proteins from denaturation at elevated temperature by sequestering them. This proposal will provide educational and training opportunities to students from graduate to high school levels in an interdisciplinary research program that spans many scientific fields such as polymer synthesis, materials chemistry, biotechnology and biology. In addition, this project will provide students with opportunity to work with industrial collaborators and receive training not only in preparing them as the future generation of scientists but also providing them with opportunities to work in industry.