Qingzhong Kong, Ph.D.

Associate Professor

Mailing Address:
11100 Euclid Ave.
Cleveland, OH 44106

phone: (216) 368-1756
fax: (216) 368-2546
email: Qingzhong.Kong@Case.edu

Biography
Dr. Qingzhong Kong graduated with B.S. and M.S degrees in Biochemistry at Nanjing University, China, in 1987 and 1990, respectively. In 1996, he 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 at Case Western Reserve University as an assistant professor. Dr. Kong is currently an tenured Associate Professor of Pathology at Case Western Reserve University, where he also holds secondary appointments at the Department of Neurology and the National Center for Regenerative Medicine.

Research
His laboratory focuses on prion diseases, functions of cellular prion protein, and muscle stem cells, including four main research areas: (1) etiology of sporadic Creutzfeldt-Jacob disease (CJD) in humans; (2) public health risks of animal prions (Chronic Wasting Disease of elk and deer, atypical Bovine Spongiform Encephalopathy of cattle, and Transmissible Mink Encephalopathy) and animal modeling of various human prion diseases (especially CJD); (3) the roles of the normal cellular prion protein in the biology and pathology of skeletal muscles and brain; and (4) muscle stem cells. His lab has 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.

Etiology of sporadic Creutzfeldt-Jacob disease (CJD)
Sporadic CJD (sCJD) is the most common prion diseases in humans, which accounts for 85-90% of all human prion cases, and there are huge diversities in sCJD phenotypes. Practically nothing is known about the etiology of sCJD. We aim to shed some light on the etiology of sCJD. The human prion protein gene (PRNP) has an octarepeat region that normally contains 4-5 octapeptide repeats. It has been reported that any increase of the octarepeat numbers to six or more or a decrease of the octarepeat number to three will lead to prion diseases in humans; numerous point-mutations in the PRNP coding region also leads to genetic prion diseases. It is conceivable that PRNP point mutations and octarepeat expansions/contractions could also accumulate in brain cells with aging. We hypothesize that, the abundance of somatic point mutations and/or octarepeat mutations in the PRNP gene increases with aging in brain cells (most likely the long-living neuronal cells), and some of the mutated brain cells will start spontaneous de novo prion replication to initiate sCJD. We have shown that the octarepeat region of the human PRNP gene is prone to expand or contract when subjected to PCR amplification in vitro and when replicated in E. coli. Intensive efforts are under way to establish highly specific and sensitive assays that are adequate for reliable detection of rare somatic pathogenic octarepeat/point mutations of the PRNP gene in brain cells from aged human subjects. We aim to use these assays to measure and compare the frequency of somatic PRNP ORF octarepeat/point mutations in brain cells from young and aged individuals and age-matched sCJD and apparently healthy non-CJD controls, with the goal of establishing a direct correlation between higher frequencies of somatic PRNP ORF mutations and sCJD.

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 indicate that the classic CWD strain is very unlikely to directly transmit to humans with the PrP-129MM genotype. We have obtained similar results for transmission of cattle or sheep-adapted CWD in humanized Tg mice. However, there have been a few reports indicating the presence of at least two CWD strains. Nothing is known about whether humans are resistant to all cervid prion strains, including naturally occurring CWD strains and prion strains adapted to cervids from other species. Also unclear is whether humans with PrP-129VV or PrP-129MV genotypes are resistant to the classic CWD strain and other cervid prion strains. We have recently demonstrated that the prion transmission species barrier from cervid to humans is prion strain-dependent and humans can be vulnerable to novel cervid prion strains. Bioassays of CWD isolates in transgenic mice expressing human PrP-129V are also under way. Furthermore, multiple subjects from CWD-endemic areas with Creutzfeldt-Jakob disease (CJD)-like phenotypes are under close examinations to determine whether zoonotic CWD transmissions in humans have already occurred.

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 (L type and H-type) were unknown. Bioassays in humanized Tg mice conducted in our laboratory and others' have shown that the BSE-L strain is more virulent than the classic BSE strain (BSE-C) in Tg mice expressing human PrP-129M. We have succeeded recently to transmit BSE-H to the humanized Tg mice as well, albeit at lower efficiency. We found that BSE-H isolates from the USA, Germany, and Poland all exhibited limited transmission in the humanized Tg mice. The USA BSE-H isolate also led to two divergent phenotypes in the humanized mice, which is reminiscent of BSE-C. We have also recently demonstrtaed that a BSE isolate carrying a genetic mutation in the PrP gene is infectious, which provides the first evidence that animals can deveop a transmissible genetic prion disease.

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. We have definitively shown that the N-terminal truncated PrP fragment is primarily generated by metalloprotease ADAM8 in 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.

Muscle stem cell
My laboratory has embarked on a major project to characterize various muscle stem cells and understand the steps and regulations of muscl stem cell differentiation.

Publications

  1. Notari S, Qing L, Pocchiari M, Dagdanova A, Hatcher K, Dogterom A, Groisman JF, Lumholtz IB, Puopolo M, Lasmezas C, Chen SG, Kong Q*, and Gambetti P*. 2012. Assessing prion infectivity of urine in sporadic Creutzfeldt-Jakob disease. Emerg Infect Dis 18(1):21-8. *Corresponding authors. PMCID: in process.
  2. Singh A, Qing L, Kong Q, Singh N. 2012. Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains. Neurobiol Dis. In press.
  3. Luo J-J, Truant AL, Kong Q, and Zou W-Q. 2012. A case study of fatal insomnia with clinical, laboratory, and genetic findings. J Clin Neurosci. In press.
  4. Li B, Qing L, Yan JQ, Kong Q. 2011. Instability of the octarepeat region of the human prion protein gene. PLoS ONE. 6(10): e26635. PMCID: PMC3197570.
  5. Dagdanova A, Ilchenko S, Notari S, Yang Q, Obrenovich ME, Hatcher K, McAnulty P, Huang L, Zou W, Kong Q, Gambetti P, Chen SG. 2010. Characterization of the prion protein in human urine. J Biol Chem. 285:30489-30495. PMCID: PMC2945542.
  6. Das D, Luo X, Singh A, Gu Y, Ghosh S, Mukhopadhyay CK, Chen SG, Sy M-S, Kong Q, and Singh N. 2010. Paradoxical role of prion protein aggregates in redox-iron induced toxicity. PLoS ONE 5(7): e11420. PMCID: PMC2897850.
  7. Zou W, Puoti G, XiaoX, Yuan J, Qing L, Cali I, Shimoji M, Langeveld JPM, Castellani R, Notari S, Crain B, Schmidt RE, Geschwind M, DeArmond SJ, Cairns N, Dickson D, Honig L, TorresJM, Mastrianni J, Capellari S, Giaccone G, Belay ED, Schonberger LB, Cohen M, Perry G, Kong Q, Parchi P, Tagliavini F, Gambetti P. 2010. Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein. Annals Neurol. 68:162-172. PMCID: PMC3032610.
  8. Zou W, Langeveld J, Xiao X, McGeer PL, Yuan J, Payne MC, Kang H-E, McGeehan J, Sy M-S, Wang G-X, Surewicz WK, Parchi P, Hoover E, Kneale G, Telling G, Kong Q, Guo J-P. 2010. PrP conformational transitions alter species preference of a PrP-specific antibody. J Biol Chem. 285:13874-84. PMCID: PMC2859550.
  9. Kim J, Cali I, Surewicz K, Kong Q, Raymond GJ, Atarashi R, Race B, Qing L, Gambetti P, Caughey B, Surewicz W. 2010. Mammalian prions generated from bacterially expressed prion protein in the absence of any mammalian cofactors. J Biol Chem 285:14083-14087. PMCID: PMC2863186.
  10. 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. PMCID: PMC2652663.
  11. 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 Path 174:1602-1608. PMCID: PMC2671249.
  12. 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. *Corresponding authors. PMCID: PMC2683871.
  13. Singh A, Kong Q, Luo X, Petersen R, Meyerson H, Singh N. 2009. Prion prion (PrP) knock-out mice show altered iron metabolism: a functional role for PrP in iron update and transport. PLoS One. 4:e6115. PMCID: PMC2699477.
  14. 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. *Corresponding authors. PMCID: PMC2268471.
  15. 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. PMCID: PMC2767200.
  16. Kong Q, Bessen R. 2008. Prion diseases (Chapter 29). In: "Neuroimmune Pharmacology". Ed. by Tsuneya Ikezu and Howard Gendelman. Springer, New York. pp403-414.
  17. 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. PMCID: PMC1871865.
  18. 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. PMCID: PMC1951779.
  19. 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. PMID: 16338930.
  20. 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. PMID: 16987816.
  21. Kong Q. 2006. RNAi: a novel strategy for treatment of prion diseases. J Clin Invest. 116:3101-3103. PMC1679715.
  22. 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. PMID: 16135751.
  23. 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.
  24. 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. PMC1461619.
  25. Kong Q*, and Maizels N. 2001. Breaksite Batch Mapping, a Rapid Method for Assay and Identification of DNA Breaksites in Mammalian Cells. Nucl Acids Res 29: e33. *Corresponding author
  26. Kong Q. and Maizels N. 1999. PMS2-deficiency diminishes hypermutation of a 1 transgene in young but not older mice. Mol Immunol 36: 83-91.
  27. Kong Q, Zhao L, Sabbaiah S, and Maizels N. 1998. A  3' enhancer drives active and untemplated somatic hypermutation of a1 transgene. J Immunol 161: 294-301.
  28. 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. PMC157057.
  29. Kong Q, Oh, J-W, and Simon AE. 1995. Symptom attenuation by a normally virulent satellite RNA of turnip crinkle virus is associated with the coat protein open reading frame. Plant Cell 7: 1625-1634. PMC161022.