The broad goal of this proposal is to develop non-invasive whole body imaging of beta cell mass (BCM) in mice with the potential for clinical translation. These agents will be used to study the progression of type I diabetes mellitus in a variety of mouse models to elucidate the etiology and progression of the disease. The candidate, Greg Thurber, has extensive experience in understanding the distribution and pharmacokinetics of imaging agents and will apply these skills to design novel agents and quantify BCM. The successful development of an imaging agent for measuring BCM would make a substantial contribution to the field of diabetes research, greatly facilitating the diagnosis, progression, and treatment intervention for the disease. The long term goal of the candidate is to develop novel imaging agents to address important biological questions in diabetes research. This work will be conducted in the Harvard/MGH Center for Systems Biology under the mentorship of Dr. Ralph Weissleder MD PhD. Since the candidate has worked with this mentor for his T32 training, he has also brought on Dr. Diane Mathis PhD and Dr. Christophe Benoist MD PhD, both experts in diabetes research, for additional mentoring and expertise. The support of Dr. Marcelo Di Carli MD in gaining insight into clinical translation will also be included in the candidate's training. These members of the advisory committee will facilitate the transition of the candidate's work away from the primary mentor to develop a successful career as an independent diabetes researcher.
The specific aims of this proposal first develop a beta cell imaging agent with optimized properties for whole body imaging followed by in vivo imaging in a variety of animal models. This work stems from preliminary research using exendin derivatives for intravital microscopy of beta cell islets. These probes have optimal pharmacokinetics for in vivo fluorescence imaging, but the additional constraints for whole body imaging, such as off target uptake and radiochemical synthesis, make these probes non-ideal. Extensive pharmacokinetic simulations show that by extending the plasma half life and reducing the dose, the target to background ratio can be improved, increasing the sensitivity of detection. Additionally, the simulations indicate the doses and imaging time points required for quantitating BCM in the context of variable delivery due to inflammation.
Specific aim 1 will develop novel probes based on the exendin peptide for beta cell targeting by reducing plasma clearance through PEGylation and/or specific albumin binding peptides. This is a well validated method for extending plasma half life and reducing renal uptake, and extensive in vitro and in vivo testing will be utilized to ensure adequate targeting.
Specific aim 2 will utilize novel tetrazine and trans-cyclo- octene chemistry to rapidly radiolabel the novel probes from aim 1 for in vivo non-invasive imaging. A variety of novel animal models for studying type 1 diabetes will be imaged with the novel probes to test the sensitivity of imaging signal to varying BCM with concurrent inflammation. If successful, these agents will allow longitudinal non-invasive imaging of BCM for any animal model of disease and can be used for monitoring progression and measuring therapeutic intervention. Furthermore, the whole body imaging enables the possible clinical translation of these agents for monitoring BCM in patients.
This project aims to create novel imaging agents for monitoring the progression of type I diabetes. If successful, these agents will allow earlier diagnosis of the disease where there is more potential for curative treatment, allow treatment monitoring, and provide a better tool for determining the effectiveness of new therapies.
|Zhang, Liang; Thurber, Greg M (2016) Quantitative Impact of Plasma Clearance and Down-regulation on GLP-1 Receptor Molecular Imaging. Mol Imaging Biol 18:79-89|
|Zhang, Liang; Navaratna, Tejas; Thurber, Greg M (2016) A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity. Bioconjug Chem 27:1663-72|
|Zhang, Liang; Bhatnagar, Sumit; Deschenes, Emily et al. (2016) Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design. Sci Rep 6:25424|
|Zhang, Liang; Navaratna, Tejas; Liao, Jianshan et al. (2015) Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands. Bioconjug Chem 26:329-37|
|Cilliers, Cornelius; Liao, Jianshan; Atangcho, Lydia et al. (2015) Residualization Rates of Near-Infrared Dyes for the Rational Design of Molecular Imaging Agents. Mol Imaging Biol 17:757-62|
|Magnuson, Angela M; Thurber, Greg M; Kohler, Rainer H et al. (2015) Population dynamics of islet-infiltrating cells in autoimmune diabetes. Proc Natl Acad Sci U S A 112:1511-6|
|Bhatnagar, Sumit; Deschenes, Emily; Liao, Jianshan et al. (2014) Multichannel imaging to quantify four classes of pharmacokinetic distribution in tumors. J Pharm Sci 103:3276-86|
|Thurber, Greg M; Reiner, Thomas; Yang, Katherine S et al. (2014) Effect of small-molecule modification on single-cell pharmacokinetics of PARP inhibitors. Mol Cancer Ther 13:986-95|
|Thurber, Greg M; Yang, Katy S; Reiner, Thomas et al. (2013) Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo. Nat Commun 4:1504|
|Thurber, Greg M; Dane Wittrup, K (2012) A mechanistic compartmental model for total antibody uptake in tumors. J Theor Biol 314:57-68|
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