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Alan P. Jasanoff and K. Dane Wittrup. Hsieh, Vivian, Ph. D. Massachusetts Institute of Technology Massachusetts Institute of Technology. Department of Chemical Engineering. Massachusetts Institute of Technology. Department of Chemical Engineering 2016-09-13T19:12:21Z 2016-09-13T19:12:21Z 2016 2016 http://hdl.handle.net/1721.1/104206 958138408 Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2016. Cataloged from PDF version of thesis. Includes bibliographical references (pages 71-84). Magnetic resonance imaging (MRI) is a powerful neuroimaging tool that allows non-invasive visualization of the brain with high spatial and temporal resolution. Research on MRI contrast agents and their application to problems in neuroscience is burgeoning, and there is particular interest in developing MRI agents that are sensitive to time varying components of neurophysiology. Relatively recent advances in biomolecular probes has demonstrated the potential and versatility of bioengineered MRI sensors for molecular imaging. However, a major limitation of these probes is the high concentration needed for imaging, which can lead to issues such as analyte buffering and toxicity, and restrict the applicability of the sensors. In this work, we explore two approaches for developing high relaxivity protein-based contrast agents to address the issues of low detectability. First, we coupled monoamine sensing with the disaggregation of superparamagnetic iron oxide nanoparticles (SPIOs). Ligand detection was imparted by integration of a monoamine sensing protein-based contrast agent derived from P450- BM3h (BM3). We demonstrated that this mechanism can produce robust signal changes of approximately 2-fold, while reducing the concentration of BM3 needed by 100-fold compared to the amount needed when only the protein is used for imaging. The second method demonstrated the feasibility of using semi-rational protein design to engineer a high relaxivity metalloprotein by tuning phenylalanine hydroxylase to bind gadolinium at high affinity. Mutations were found that increased the protein affinity by two orders of magnitude and enhanced relaxivity. The results of this thesis advance approaches for creating high relaxivity contrast agents which can be applied to the development of probes for other analytes, ultimately advancing and broadening the applicability of bioengineered probes in molecular functional neuroimaging. by Vivian Hsieh. Ph.D. 93 pages eng Massachusetts Institute of Technology M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 Chemical Engineering. High relaxivity biomolecule based contrast agents engineered for molecular functional magnetic resonance imaging Thesis application/pdf Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="d84616e2-68c5-43a4-96bd-dbe6c78b9e15"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>High relaxivity biomolecule based contrast agents engineered for molecular functional magnetic resonance imaging</Title> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2016</PublicationDate> <Authors> <Author> <DisplayName>Hsieh, Vivian, Ph. D. Massachusetts Institute of Technology</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Chemical Engineering.</Keyword> <Abstract>Magnetic resonance imaging (MRI) is a powerful neuroimaging tool that allows non-invasive visualization of the brain with high spatial and temporal resolution. Research on MRI contrast agents and their application to problems in neuroscience is burgeoning, and there is particular interest in developing MRI agents that are sensitive to time varying components of neurophysiology. Relatively recent advances in biomolecular probes has demonstrated the potential and versatility of bioengineered MRI sensors for molecular imaging. However, a major limitation of these probes is the high concentration needed for imaging, which can lead to issues such as analyte buffering and toxicity, and restrict the applicability of the sensors. In this work, we explore two approaches for developing high relaxivity protein-based contrast agents to address the issues of low detectability. First, we coupled monoamine sensing with the disaggregation of superparamagnetic iron oxide nanoparticles (SPIOs). Ligand detection was imparted by integration of a monoamine sensing protein-based contrast agent derived from P450- BM3h (BM3). We demonstrated that this mechanism can produce robust signal changes of approximately 2-fold, while reducing the concentration of BM3 needed by 100-fold compared to the amount needed when only the protein is used for imaging. The second method demonstrated the feasibility of using semi-rational protein design to engineer a high relaxivity metalloprotein by tuning phenylalanine hydroxylase to bind gadolinium at high affinity. Mutations were found that increased the protein affinity by two orders of magnitude and enhanced relaxivity. The results of this thesis advance approaches for creating high relaxivity contrast agents which can be applied to the development of probes for other analytes, ultimately advancing and broadening the applicability of bioengineered probes in molecular functional neuroimaging.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>