The proposed interdisciplinary study allows the candidate to further develop his knowledge and expertise in magnetic resonance (MR) molecular imaging and Alzheimer's disease (AD), while providing rigorous exposure to the biomedical aspects of the research project. The goal is to increase the candidate's expertise in multiple areas necessary to his proposed research project and future career development. These areas include neurology, neurodegenerative disease, histology, molecular and cellular biology, optical imaging, small animal imaging, and contrast agent chemical synthesis and characterization. This award will provide the guidance and training necessary for the candidate to become a successful, independent researcher. A major goal in Alzheimer's disease research has been to develop quantitative measurements that reflect the underlying neuropathological process. While some promising headway has been made in identifying biomarkers in cerebral spinal fluid, they fall short of providing a direct link to the AD related brain changes that will be the targets of therapeutic intervention.
The aim of this proposal is to develop MR contrast agent probes for specific biomarkers of neuronal structure and function that could provide such a direct measure of AD brain changes. In particular, MR molecular imaging techniques and contrast agents will be developed for the in-vivo imaging of beta-amyloid (A-beta) and the expression of genes that play crucial roles in memory formation, which have been shown to be suppressed in AD. Well-characterized Amyloid Precursor Protein (APP) transgenic mouse models of AD will be utilized to test the efficacy of these novel imaging techniques and contrast agents. These studies will also help to identify and test potential therapeutic agents that regulate amyloid levels and/or restore normal gene expression levels.
The specific aims of the proposal are to: (1) develop improved MR imaging techniques for imaging targeted iron-oxide nanoparticle based molecular imaging contrast agents;(2) develop sensitive iron-oxide based contrast agents that specifically bind A-beta;(3) develop oligodeoxynucleotide tagged iron-oxide contrast agents that will enable the imaging of mRNA expression levels of activity-regulated cytoskeleton- associated protein (Arc), an important protein involved in neuronal structure and function.
|Farrar, Christian T; William, Christopher M; Hudry, Eloise et al. (2014) RNA aptamer probes as optical imaging agents for the detection of amyloid plaques. PLoS One 9:e89901|
|Huang, Shuning; Kim, Jeong Kon; Atochin, Dmitriy N et al. (2013) Cerebral blood volume affects blood-brain barrier integrity in an acute transient stroke model. J Cereb Blood Flow Metab 33:898-905|
|Emblem, Kyrre E; Mouridsen, Kim; Bjornerud, Atle et al. (2013) Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med 19:1178-83|
|Snuderl, Matija; Batista, Ana; Kirkpatrick, Nathaniel D et al. (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065-76|
|Kodack, David P; Chung, Euiheon; Yamashita, Hiroshi et al. (2012) Combined targeting of HER2 and VEGFR2 for effective treatment of HER2-amplified breast cancer brain metastases. Proc Natl Acad Sci U S A 109:E3119-27|
|Farrar, Christian T; Kamoun, Walid S; Ley, Carsten D et al. (2011) Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model. PLoS One 6:e17228|
|Koffie, Robert M; Farrar, Christian T; Saidi, Laiq-Jan et al. (2011) Nanoparticles enhance brain delivery of blood-brain barrier-impermeable probes for in vivo optical and magnetic resonance imaging. Proc Natl Acad Sci U S A 108:18837-42|
|Farrar, Christian T; Kamoun, Walid S; Ley, Carsten D et al. (2010) In vivo validation of MRI vessel caliber index measurement methods with intravital optical microscopy in a U87 mouse brain tumor model. Neuro Oncol 12:341-50|
|Chae, Sung-Suk; Kamoun, Walid S; Farrar, Christian T et al. (2010) Angiopoietin-2 interferes with anti-VEGFR2-induced vessel normalization and survival benefit in mice bearing gliomas. Clin Cancer Res 16:3618-27|
|Blackwell, Megan L; Farrar, Christian T; Fischl, Bruce et al. (2009) Target-specific contrast agents for magnetic resonance microscopy. Neuroimage 46:382-93|
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