Christina H. Liu, PhD/PE
RESEARCH INTERESTS
My primary research interests focus the use of magnetic resonance imaging (MRI) to assess and track acute and permanent biomarkers of neurological development and/or disorders at the gross and microscopic levels in vivo, and to correlate these parameters to behavioral outcomes in live rodents (mice and rats). Currently, my laboratory is involved in several animal model studies that fall into two categories: drug addiction and cerebral ischemia.
For structural assessment of normal and diseased brains, I have utilized both conventional and advanced MRI techniques: (1) Conventional T1 or T2 MR imaging to detect anatomical delineations of brain atrophy, and (2) diffusion-weighted and diffusion tensor imaging to assess early brain injuries at the cellular level and to predict/track white matter deterioration after chronic recovery.
To perform functional assessment of the brains, I have utilized advanced MRI methods such as (1) manganese-enhanced MRI (MEMRI) for direct assessment of neuronal activation, and (2) functional/pharmacological MRI (fMRI/phMRI) for indirect assessment of neuronal activation by addictive drugs, using an intravascular iron-oxide nanoparticles (IRON) technique for cerebral blood volume (CBV) measurements and subsequent parametric map construction using mathematical models.
For brain studies at the microscopic level, my laboratory has developed a novel MRI technique to detect nucleic acids in live animal brains. This technique permits quantitative imaging, targeting, labeling, and manipulation of genetic material including gene transcripts (PCT/US2005/029875) and DNA binding proteins (patent pending, MGH-3204) in living cells. As such, it represents an area of research poised to become the next frontier of MRI. The invention involves making a complex composed of phosphorothioate-modified oligodeoxynucleotides (sODN) complementary to a specific endogenous mRNA sequence and an MR contrast agent, superparamagnetic iron oxide nanoparticles (SPION). Our studies in male C57black6 mice (or rats) have shown that the probe complex (SPION-sODN) can be delivered to the brain by intracerebroventricular (ICV) or intraperitoneal (i.p.) infusion, or by eye-drop solution to the ocular sac (patent pending, MGH-3395). Probe delivery and retention are detected by MRI in live, anesthetized animals and confirmed by histological and immunohistochemical methods. Specifically, we have demonstrated that the probe complex was intact by showing the co-localization of intracellular iron (via iron stains) and sODN (via immunohistochemistry) in brain tissue hours to 1 day after probe infusion. Furthermore, we have demonstrated the target specificity of this probe complex using in situ reverse transcription-polymerase chain reaction without the addition of the specific primer.
Applications of this novel technique for live cerebral gene detection in my laboratory include:
- Detection of biomarkers for drug addiction: My laboratory has special SPION-sODN probes (targeting mRNA of c-fos, fosB, and ΔfosB) that enable in vivo MR detection of drug-induced gene up-regulation in acutely and chronically amphetamine-exposed mouse brains. Although amphetamine and its derivatives are the best known psychostimulants in our society, the mechanism underlying addictive behavior after repeated exposure to such substances is poorly understood. Our laboratory has demonstrated that while c-fos and fosB mRNAs are transiently up-regulated in a regionally specific manner after acute amphetamine injection, ΔfosB mRNA is elevated in the same regions as c-fos and fosB mRNAs after chronic exposure, withdrawal, and re-introduction of amphetamine. These results are consistent with studies done by other investigators using animal models of repeated drug exposure, which have strongly implied that ΔFosB protein is the “molecular switch” for drug addiction.
- Detection of biomarkers for neuronal injury and/or repair: By introducing an acute insult such as transient global ischemia and reperfusion, our laboratory tracks the pathogenesis of the injured brain. We first assess and characterize regions of metabolic disturbance one day after injury using diffusion-weighted imaging and parametric maps of apparent diffusion coefficients. Once we have identified the regions of interest, we study the longitudinal effects in these regions for up to 12 weeks, alternating examinations of the following: blood-brain barrier (BBB) leakage (using Gd-MRI), metalloproteinase-9 expression (using SPION-mmp9), glosis (using SPION-gfap), and angiogenesis (using SPION-bactin). Because the BBB has appeared to remain leaky for up to 8 weeks after the initial ischemic insult, we have been able to deliver the SPION-sODN probe non-invasively, via intraperitoneal (ip) or ocular routes, at multiple time points in the same animal.
My laboratory has begun to investigate the behavioral outcomes after prolonged exposure to addictive drugs and chronic recovery after global ischemic insults to the brain. We use several behavioral techniques including a locomotor box, Morris water maze, pole test, and corner test to assess specific brain function and cognitive deficits that may result in behavioral alterations in these mice. My goal is to use the novel in vivo MRI technique mentioned above to link the modulation of endogenous genetic fingerprints in response to external insults or stimuli to concurrent or subsequent behavioral alterations, which may become a power tool for determining clinical prognosis and appropriate medical interventions for neurological disorders.
This ongloing work is supported by NIDA, NCRR, the American Heart Association).
