Philip K. Liu

Summary

Summary:
The goal of my research is to develop and apply gene transcript (GT)-targeting MRI (GT-tMRI) in animal neurological disorder models to enable in vivo detection and targeting of neural cells that express specific genetic marks. Specifically, this work is aimed at bringing molecular biology techniques to medicine, for diagnostic and interventional strategies that avoid reliance on biopsies. This technology, which is based on a standard MR-visible T2 contrast agent attached to a small single-stranded DNA sequence, has been developed over several years of training and research. I received valuable initial exposure to the genetic theory of carcinogenesis as a graduate student at Michigan State University (Drs. CC Chang and JE Trosko), and as a postdoctoral fellow at the University of Washington, Seattle, WA, I intensified my training under Dr. LA Loeb, with whom I learned the mutator theory of cancer and aging (somatic cell genetics). I carried out DNA polymerase purification, gene transfer from mutator mutant to normal human cells under a National Research Service Award, and later, a New Investigator Award from NCI. At the Department of Environmental Health Sciences at Case Western Reserve University, Cleveland, OH, I taught graduate students and expanded my research as PI of an NSF research grant to study cell cloning of a mutant rodent cell line that underproduces DNA polymerase, applying molecular imaging to show ongoing DNA repair and quantification of DNA polymerase in cell culture conditions. At the University of Texas, MD Anderson Cancer Center, I worked as Technical Director of the DNA Diagnostic Laboratory, where we specialized in cancer cell typing using unique DNA hybridization ex vivo. At Baylor College of Medicine, I established myself in neuroscience as PI of an NIH-funded R01 and on an Established Investigator grant funded by the American Heart Association. It was with this project that I laid the groundwork for the research proposed in this application, by developing effective strategies in live rodents for gene knockdown, mRNA binding and cell targeting in the living brains of rats. I relocated to Boston in 2003, and took a position at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital (MGH), I led another NIH R01-funded project that led to the design of the patent-pending GT-tMRI technology. Using this novel technology we have demonstrated and independently validated fosB desensitization at the mRNA level in live mouse brains after chronic amphetamine exposure. This experience allows us to carry out in vivo GT-tMRI and cell targeting in different models of neurological disorders for gliosis and angiogenesis. We have developed several MR contrast agents for biomarkers including mRNA of Actin, cFos, FosB, delta FosB, histone deacetylase, glial fibrillary acidic protein, Iba1, matrix metalloproteinase and Nestin.
Grants:
1R01DA029889-01 (PI: PK Liu) 07/01/2010

Publications

  1. ncbi request reprint Transcription MRI: a new view of the living brain
    Philip K Liu
    Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    Neuroscientist 14:503-20. 2008
  2. doi request reprint Gene targeting MRI: nucleic acid-based imaging and applications
    Philip K Liu
    Department of Radiology, AA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA
    Methods Mol Biol 711:363-77. 2011
  3. pmc Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations
    P K Liu
    Division of Laboratory Medicine, Department of Tumor Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA
    Oncogene 12:2267-78. 1996
  4. pmc Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion
    P K Liu
    Laboratory of Neurobiology, Division of Restorative Neurology and Human Neurobiology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci 16:6795-806. 1996
  5. pmc Oxidative damage to the c-fos gene and reduction of its transcription after focal cerebral ischemia
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 73:1164-74. 1999
  6. pmc Up-regulation of base excision repair activity for 8-hydroxy-2'-deoxyguanosine in the mouse brain after forebrain ischemia-reperfusion
    L H Lin
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 74:1098-105. 2000
  7. pmc Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    FASEB J 14:955-67. 2000
  8. pmc Neuronal NOS inhibitor that reduces oxidative DNA lesions and neuronal sensitivity increases the expression of intact c-fos transcripts after brain injury
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Tex 77030, USA
    J Biomed Sci 8:336-41. 2001
  9. pmc DNA-based MRI probes for specific detection of chronic exposure to amphetamine in living brains
    Christina H Liu
    Laboratory for Gene Transcript Targeting, Imaging and Repair, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 29:10663-70. 2009
  10. pmc Homogeneous repair of nuclear genes after experimental stroke
    N Moore
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 80:111-8. 2002

Collaborators

Detail Information

Publications22

  1. ncbi request reprint Transcription MRI: a new view of the living brain
    Philip K Liu
    Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    Neuroscientist 14:503-20. 2008
    ..Transcription MRI will lend itself to myriad applications in living organs...
  2. doi request reprint Gene targeting MRI: nucleic acid-based imaging and applications
    Philip K Liu
    Department of Radiology, AA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA
    Methods Mol Biol 711:363-77. 2011
    ..We have established a workable and reproducible MRI technique in live rodent brains...
  3. pmc Analysis of genomic instability in Li-Fraumeni fibroblasts with germline p53 mutations
    P K Liu
    Division of Laboratory Medicine, Department of Tumor Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA
    Oncogene 12:2267-78. 1996
    ..Such an activity, which is likely to be due to the p53(mut), could result in the high rate of chromosomal instability and allelic loss of the wild-type p53 observed as these cells spontaneously immortalize...
  4. pmc Damage, repair, and mutagenesis in nuclear genes after mouse forebrain ischemia-reperfusion
    P K Liu
    Laboratory of Neurobiology, Division of Restorative Neurology and Human Neurobiology, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci 16:6795-806. 1996
    ..These genes became resistant to the glycosylase within 4-6 hr of reperfusion, suggesting a reduction in DNA damage and presence of DNA repair in nuclear genes. These results suggest that nuclear genes could be targets of free radicals...
  5. pmc Oxidative damage to the c-fos gene and reduction of its transcription after focal cerebral ischemia
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 73:1164-74. 1999
    ..01). Our results suggest that inhibiting nNOS partially attenuates FCIR-induced oxidative damage and that nNOS or other mechanisms induce nuclear gene damage that interferes with gene transcription in the brain...
  6. pmc Up-regulation of base excision repair activity for 8-hydroxy-2'-deoxyguanosine in the mouse brain after forebrain ischemia-reperfusion
    L H Lin
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 74:1098-105. 2000
    ..The data suggest a possibility that the OGG1 protein may excise oh8dG in the mouse brain and that the activity of OGG1 may have a functional role in reducing oxidative gene damage in the brain after FblR...
  7. pmc Oxidative DNA damage precedes DNA fragmentation after experimental stroke in rat brain
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    FASEB J 14:955-67. 2000
    ..Therefore, the oxidative DNA lesions observed in the nuclear and mitochondrial DNA of the brain are different from the DNA fragmentation detected using TUNEL...
  8. pmc Neuronal NOS inhibitor that reduces oxidative DNA lesions and neuronal sensitivity increases the expression of intact c-fos transcripts after brain injury
    J Cui
    Department of Neurosurgery, Baylor College of Medicine, Houston, Tex 77030, USA
    J Biomed Sci 8:336-41. 2001
    ..p.), known to abolish nitric oxide, gene damage and neuronal sensitivity, was injected. Our data suggest that neuronal nitric oxide synthase and aberrant mRNA from genes with oxidative damage could be associated with neuronal sensitivity...
  9. pmc DNA-based MRI probes for specific detection of chronic exposure to amphetamine in living brains
    Christina H Liu
    Laboratory for Gene Transcript Targeting, Imaging and Repair, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 29:10663-70. 2009
    ..The in vivo target specificity of these probes permits reliable MRI visualization of AMPH-induced differential elevations of fosB and Delta fosB mRNA in living brains...
  10. pmc Homogeneous repair of nuclear genes after experimental stroke
    N Moore
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurochem 80:111-8. 2002
    ..The result indicates that genomic repair of ODLs in the brain did not significantly incorporate BrdU, and the initiation of neurogenesis probably starts after the completion of repair in the brain...
  11. pmc Transcripts of damaged genes in the brain during cerebral oxidative stress
    Philip K Liu
    Department of Neurosurgery, Baylor College of Medicine, Houston, Texas 77030, USA
    J Neurosci Res 70:713-20. 2002
    ..Understanding this mechanism could lead to the development of therapeutic techniques (physiologic, pharmacological, and/or genomic) that can enhance recovery...
  12. pmc Ischemia-reperfusion-related repair deficit after oxidative stress: implications of faulty transcripts in neuronal sensitivity after brain injury
    Philip K Liu
    Departments of Neurosurgery and Molecular and Cell Biology and Cardiovascular Disease Program of the Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
    J Biomed Sci 10:4-13. 2003
    ..This suggests that the accuracy of gene expression could be accounted for the recovery of cellular function after cerebral injury...
  13. pmc Suppression of ischemia-induced fos expression and AP-1 activity by an antisense oligodeoxynucleotide to c-fos mRNA
    P K Liu
    Division of Restorative Neurology and Human Neurobiology, Baylor College of Medicine, Houston, TX 77030
    Ann Neurol 36:566-76. 1994
    ..These results support the hypothesis that increased AP-1 binding activity following focal cerebral ischemia is dependent on Fos expression and can be inhibited in vivo by antisense c-fos oligodeoxynucleotides...
  14. pmc Imaging cerebral gene transcripts in live animals
    Christina H Liu
    Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 27:713-22. 2007
    ..These results demonstrated that SPION-sODN conjugates can detect active transcriptions of specific mRNA species in living animals with MRI...
  15. pmc MR contrast probes that trace gene transcripts for cerebral ischemia in live animals
    Christina H Liu
    AA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA
    FASEB J 21:3004-15. 2007
    ..This study should enable MR detection of mRNA alteration in disease models of the central nervous system...
  16. pmc Forebrain ischemia-reperfusion simulating cardiac arrest in mice induces edema and DNA fragmentation in the brain
    Christina H Liu
    A A Martinos Center for Biomedical Imaging Charlestown, MA, USA
    Mol Imaging 6:156-70. 2007
    ..These findings suggest that brain injury induced by cardiac arrest can be detected in live animals...
  17. ncbi request reprint Oxidative DNA lesions in a rodent model of traumatic brain injury
    Donna R Mendez
    Department Pediatrics Emergency Medicine, Baylor College of Medicine, Houston, Texas, USA
    J Trauma 56:1235-40. 2004
    ..Oxidative DNA lesions have not been well studied in traumatic brain injury (TBI)...
  18. pmc Ischemic injury and faulty gene transcripts in the brain
    P K Liu
    Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, USA
    Trends Neurosci 24:581-8. 2001
    ..These findings open the possibility of applying genetic tools to identify molecular mechanisms of gene repair and to derive new therapies for stroke and brain injury...
  19. pmc Epigenetics of amphetamine-induced sensitization: HDAC5 expression and microRNA in neural remodeling
    Philip K Liu
    Department of Radiology, Molecular Contrast Enhanced MRI Laboratory at the Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital and the Harvard Medical School, CNY149 2301 Thirteenth Street, Charlestown, MA, 02129, USA
    J Biomed Sci 23:90. 2016
    ..To validate the MRI results we used ex vivo methods including in situ hybridization, RT-PCR, immunohistochemistry, and transmision electron microscopy...
  20. pmc Intracellular gene transcription factor protein-guided MRI by DNA aptamers in vivo
    Christina H Liu
    3Massachusetts General Hospital, CNY149 2301 Thirteenth St, Charlestown, MA 02129, USA
    FASEB J 28:464-73. 2014
    ....
  21. pmc MRI reveals differential effects of amphetamine exposure on neuroglia in vivo
    Christina H Liu
    Athinoula A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    FASEB J 27:712-24. 2013
    ..The results enable us to conclude that amphetamine induces toxicity to neuroglia in vivo, which may cause remodeling or reconnectivity of neuroglia...
  22. pmc Noninvasive detection of neural progenitor cells in living brains by MRI
    Christina H Liu
    A A Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
    FASEB J 26:1652-62. 2012
    ..03 mm(3). The presence of electron-dense nanoparticles in vascular pericytes in the region of BBB injury led us to draw the conclusion that GT-tMRI can noninvasively reveal neural progenitor cells during vascularization...

Research Grants3

  1. In vivo Profiling of Glial and Neuronal Activities in Psychostimulant Abuse
    Philip K Liu; Fiscal Year: 2010
    ..Such enhancement will bring a step closer to real-time analysis of neurophysiologic events that occur in patients with substance abuse and addiction. ..
  2. Gene Repair in signal Transduction after CNS Injury
    Philip Liu; Fiscal Year: 2006
    ..abstract_text> ..
  3. Neurovascular Mechanisns of Brain Function and Disease
    Philip Liu; Fiscal Year: 2008
    ..The immediate goal is to show our probe can report the elevation of gene transcripts after cerebral ischemia. [unreadable] [unreadable] [unreadable]..