 |
Qingzhong Kong, Ph.D.Associate ProfessorMailing Address: email: Qingzhong.Kong@Case.edu |
Biography
Dr. Qingzhong Kong graduated with a B.S. in Biochemistry at Nanjing University, China, in 1987. He went on
to earn an M.S. in Molecular Biology. In 1996, Dr. Kong completed a Ph.D. in Molecular Virology at
the University of Massachusetts. From 1996 to 2000, he was a Research Associate in Molecular Immunology at
Yale University, after which he joined the Department of Pathology as an assistant professor. Dr. Kong
is currently an Associate Professor of Pathology and he has a secondary appointment at the Department
of Environmental Health Science.
Research
My laboratory currently has three main research areas: (1) public health risks of animal prions
(Chronic Wasting Disease of elk and deer, atypical Bovine Spongiform Encephalopathy of cattle, and scrapie
of sheep/goats) and animal modeling of various human prion diseases; (2) the roles of the normal cellular
prion protein in the biology and pathology of skeletal muscles and brain; and (3) gene therapy and
vaccination using non-viral DNA and muscle stem cells. We have created dozens of transgenic mouse lines
for the above research areas, some of which are inducible by doxycycline or conditional when used with
Cre recombinase expressing mice. The following is a brief summary for some of the major projects.
Chronic Wasting Disease (CWD)
CWD is a widespread prion disease of cervids (elk, deer, and moose) in USA and Canada. Many people have
been exposed to CWD, but its human transmissibility is unknown. We have conducted experimental
transmissions of CWD from elk, mule deer, and white-tailed deer in humanized and cervidized transgenic
(Tg) mouse models. Our data shows that CWD is very unlikely to transmit to humans directly, but the
inoculated CWD prion could likely persist for a long time in the brain of affected human subjects despite
the lack of detectable pathogenic PrP (named PrPSc) or histopathology consistent with prion infection. We
have also obtained complete data on transmission of cattle or sheep-adapted CWD in humanized Tg mice, and
the results suggest a very low transmissibility in humans (if any at all) as well. In addition,
serial passages of CWD isolates from elk, mule deer and white-tailed deer in the cervidized Tg mice
suggesting that CWD prions from the above three cervid species are the same CWD strain. Furthermore,
several subjects from CWD-endemic areas with sporadic Creutzfeldt-Jakob disease (CJD)-like phenotypes are
under close examinations to determine whether their prion diseases were acquired from CWD. Surprisingly,
we also found that the glycoform pattern and molecular weight of protease-resistant PrPSc, which are
considered hallmarks a prion strain, could change in a host with different PrP, but the changes are
reversible. This finding will have significant ramifications in studying cross-species prion
transmissions, and it poses a challenge to the current theory that the prion strains are encoded by
PrPSc conformations. We also found that Creutzfeldt-Jacob disease (CJD) prion adapted in the cervidized
mice could easily infect the humanized Tg mice, indicating that other prion strains crossed into cervids or
new naturally occurring CWD strains might be highly transmissible to humans. In fact, a couple of
recent reports from other laboratories that tested different CWD isolates have suggested the presence of
more than one CWD strain, and we are in the process of evaluating the public health risks from these “new”
CWD strains.
Atypical Bovine Spongiform Encephalopathy (BSE): transmissibility and phenotypes in humans
Classical BSE is known to cause the so-called “new variant CJD” in humans, but the transmission risk
and potential features in humans of the recently discovered atypical BSE strains are unknown. My lab
started to address this critical and urgent public health issue immediately after the report of the
first atypical BSE cases in 2004. We have recently published our results on the human transmissibility of
one of the atypical BSE strains (named BASE or BSE-L), which show that BASE is more virulent than classical
BSE and the phenotype and characteristics of BASE-infected humanized Tg mice are distinct from known
human prion diseases. Two atypical BSE isolates found in the USA and other atypical BSE strains from
Europe are also under examination in several humanized Tg models representing the three major human
prion protein (PrP) genotypes. Very interesting preliminary results have been obtained.
Prion protein (PrP) and muscle biology and diseases
The PrP level has been reported to be elevated in the muscles from patients with a series of muscle diseases
as well as from several animal models for muscle diseases, but the role of PrP in muscular diseases
was unclear. My lab has created highly doxycycline-inducible Tg mouse lines and proved for the first time
that over-expression of wild type PrP in the skeletal muscles alone is sufficient to cause a myopathy, and
the disease is correlated with preferential accumulation of an N-terminal truncated PrP fragment in
skeletal muscle cells. Further experiments using microarray and other tools revealed the involvement
of specific metalloproteases and p53 in PrP-mediated myopathy. We also found that PrP regulates
muscle differentiation. We are expanding our efforts to understand the roles and underlying mechanisms of
the normal cellular PrP in muscle biology and muscle and nervous system disorders.
Gene Therapy and DNA Vaccination
My laboratory recently initiated a major project, aiming to develop safe and effective non-viral DNA
and autologous primary muscle stem cell-based gene therapies for inherited muscle diseases and many
other diseases (such as cancer) as well as DNA vaccines. We have established a DNA vector that allows
for highly doxycycline-inducible, skeletal muscle-specific gene expression in transgenic mice. We are
trying to develop this vector into a non-viral DNA vaccination and gene therapy tool to treat rare
inherited muscle diseases and other diseases either directly with naked DNA or indirectly through
modified autologous primary muscle stem cells.
Publications
Liang J, Parchaliuk D, Medina S, Sorensen G, Landry L, Huang S, Wang M, Huang S, Kong Q, Booth S.
2009. PrP-mediated myopathy involves the induction of p53-regulated signaling pathways: A microarray
analysis. BMC Genomics. 10:201.
Xiao X, Miravalle L, Yuan J, McGeehan J, Dong Z, Wyza R, MacLennan GT, Golichowski AM, Kneale G, King N, Kong Q, Spina S, Vidal R, Ghetti B, Roos K, Gambetti P, Zou W. 2009. Failure to detect the presence of prions in the uterine and gestational tissues from a gravida with Creutzfeldt-Jakob disease. Amer J Pathol. 174:1602-1608.
Singh A, Isaac AO, Luo X, Mohan ML, Cohen ML, Chen F, Kong Q, Bartz J, and Singh N. 2009. Abnormal brain iron homeostasis in human and animal prion disorders. PLoS Pathogens. 5-e1000336.
Gambetti P, Dong Z, Yuan J, Xiao X, Zheng M, Alshekhlee A, Castellani R, Cohen M, Barria MA, Gonzalez-Romero D, Belay ED, Schonberger LB, Marder K, Harris C, Burke JR, Montine T, Wisniewski T, Dickson DW, Soto C, Hulette CM, Mastrianni JA, Kong Q, Zou WQ. 2008. A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol. 63:697-708.
Kong Q, Zheng M, Casalone C, Qing L, Huang S, Chakraborty B, Wang P, Cali I, Chen F, Corona C, Martucci F, Iulini B, Acutis P, Wang L, Liang J, Wang M, Li X, Monaco S, Zanusso G, Zou W, Caramelli M, Gambetti P. 2008. Evaluation of the human transmission risk of an atypical bovine spongiform encephalopathy prion strain. J Virol. 82:3697-3701.
Basu S, Mohan ML, Luo X, Kundu B, Kong Q, Singh N. 2007. Modulation of proteinase K-resistant PrP in cells and infectious brain homogenate by redox-iron: Implications for prion replication and disease pathogenesis. Mol Biol Cell. 18:3302-12.
Huang S, Liang J, Zheng M, Li X, Wang M, Wang P, Vanegas D, Wu D, Chakraborty B, Hays AP, Chen K, Chen SG, Cohen M, Booth S, Gambetti P, and Kong Q. 2007. Regulated over-expression of PrP in the skeletal muscles leads to myopathy in transgenic mice. Proc Natl Acad Sci USA. 104: 6800-5.
Yuan J, Xiao X, McGeehan J, Dong Z, Cali I, Fujioka H, Kong Q, Kneale G, Gambetti P, and Zou W-Q. 2006. Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains. J Biol Chem. 281:34848-58.
Xie Z, O’Rourke KI, Dong Z, Jenny AL, Langenberg J, Belay ED, Schonberger LB, Petersen RB, Zou W, Kong Q, Gambetti P, and Chen SG. 2006. Chronic Wasting Disease of elk and deer and Creutzfeldt-Jakob disease: Comparative analysis of scrapie prion protein. J Biol Chem. 281: 4199-4206.
Kong Q, Huang S, Zou W, Vanegas D, Wang M, Wu D, Yuan J, Bai H, Zheng M, Deng H, Chen K, Jenny AL, O'Rourke K, Belay ED, Schonberger LB, Petersen RB, Sy M-S, Chen SG, and Gambetti P. 2005. Chronic wasting disease of elk: Transmissibility to humans examined by transgenic mouse models. J Neurosci. 25:7944-7949.
Kong Q, Surewicz WK, Petersen RB, Zou W, Chen SG, and Gambetti P, Parchi P, Capellari S, Goldfarb L, Montagna P, Lugaresi E, Piccardo P, and Ghetti B. 2004. Inherited prion diseases (Chapter 14). In "Prion biology and diseases (2nd Ed)". Ed. by Stanley Prusiner. Cold Spring Harbor Laboratory Press, New York. pp673-776.
Kong Q and Maizels N. 2001. Breaksite Batch Mapping, a Rapid Method for Assay and Identification of DNA Breaksites in Mammalian Cells. Nucleic Acids Research 29: e33.
Kong Q and Maizels N. 2001. DNA Breaks in Hypermutating Immunoglobulin Genes: Evidence for a Break-and- Repair Pathway of Somatic Hypermutation. Genetics 158: 369-378.
Kong Q and Maizels N. 1999. PMS2-deficiency diminishes hypermutation of a λ1 transgene in young but not older mice. Mol Immunol. 36: 83-91.
Kong Q, Zhao L, Sabbaiah S, and Maizels N. 1998. A &lambda 3′ enhancer drives active and untemplated somatic hypermutation of a l1 transgene. J Immunol. 161: 294-301.
Kong Q, Wang J, and Simon AE. 1997. Satellite RNA-mediated resistance to turnip crinkle virus in Arabidopsis involves a reduction in virus movement. Plant Cell 9: 2051-2063.