Molecular Oncology and Biomarkers


Dimitrios Moskofidis, MD

Dimitrios Moskophidis, MD, PhD

Molecular Oncology and Biomarkers Program
Professor Medicine
Professor, Biochemistry and Molecular Biology
Professor of Graduate Studies

 


Georgia Cancer Center
1410 Laney-Walker Blvd., CN 3143
Phone:
706-721-8738 office 706-721-8883 laboratory
DMOSKOFIDIS@augusta.edu

RESEARCH SUMMARY

The scope of my research includes studies on immune regulation, microbial (viral) pathogenesis, and inflammation as well as studies on protein homeostasis and molecular chaperone biology/function in cancer promotion and the progression of neurodegenerative diseases. These are areas of great medical importance, and there is reasonable expectation that this research will continue to provide the rationale to develop novel strategies to prevent, and perhaps more effectively treat, viral infectious diseases as well as patients with cancer and with age-related neurodegenerative diseases.

RESEARCH INTERESTS

The primary focus of research in my laboratory, over the past two decades, has been to investigate microbial (viral) pathogenesis and immunology/inflammation, as well as mechanisms of protein homeostasis and molecular chaperone biology. In addition to elucidating basic mechanisms of viral pathogenesis, a major focus of our research is on the mechanisms of chaperone-mediated cancer promotion. These are areas of great medical importance, and there is reasonable expectation that this research will continue to provide the rationale to develop novel strategies to prevent, and perhaps more effectively treat, viral infectious diseases and cancer. The specific research areas can be summarized as follows:

Function of molecular chaperones and heat shock transcription factors in mouse models of human diseases (cancer)
This research area involves the study of cellular processes via which molecular chaperones mediate the host response to environmental stress and the role of these processes in human diseases such as cancer. One approach has focused on studying the function of these molecules in knockout mouse models. In my laboratory, the development and functional analyses of several conditional knockout mouse models – including the major members of the HSP70 and HSP90 families in the endoplasmic reticulum (GRP78, GRP170, SIL1, GRP94), cytoplasm (HSP70, HSC70, HSP25), and mitochondria (GRP75) – provide important materials for innovative research in the cancer biology field. Although several studies are in progress, publications from my laboratory on the functional characterization in situ of the stress-induced HSP70 and HSP25 chaperone proteins rank among the important contributions to chaperone and cancer biology research. Another important contribution was our discovery that the ability of HSF1 to promote malignant cell transformation resides in its ability to stimulate transcription of mRNAs that encode proteins regulating adaptive energetic and metabolic pathways. Targeting inactivation of HSF1 interferes with the anabolic malignant state and is an effective strategy for prevention and therapy of several cancer types. Notably, this important research is the result of a long-term collaboration with Dr. N. Mivechi at the Georgia Cancer Center.

 Deciphering the fundamental mechanisms coordinating the immune response to acute versus persistent viral infections and the implications in cancer immune evasion
Persistent viral infections create conditions for long-term pathologic consequences in human populations. A specific focus of my laboratory has been to elucidate the mechanisms by which viruses persist and escape immune surveillance. This research is important for our understanding of viral pathogenesis and for the development of measures to control and eliminate such infections and the diseases they cause. Our original observations) have provided proof-of-concept that:

  1. The evolution of the immune system has developed regulatory mechanisms to ensure efficient clearance of an infection with minimal damage to host tissues. Specifically, we discovered that during a rapidly spreading viral infection, the initially induced virus-specific CD8+T cells fail to contain the infection as a result of progressive functional loss and physical elimination. This phenomenon, called “T cell exhaustion,” represents an important aspect in the regulation of protective immune responses. This observation has not only provided an avenue for studying interactions between viruses and the immune system in the context of acute or persistent infections, but also has stimulated innovative research on mechanisms facilitating malignant cell evasion from immune-mediated surveillance.

Viruses persist in an immune population, as in the case of influenza, or in an individual, as postulated for HIV, when they are able to escape neutralizing antibodies by changing their antigens. This has been known since the original discovery in the 1980s that revealed that the evolution of influenza viruses is associated with the generation of antibody-resistant viral strains. We made the original discovery that viruses can escape surveillance by virus-specific T cells through introducing mutations in their genomes that alter the presentation of antigen-specific T cell epitopes. Since T cell-mediated immunity represents a critical defense mechanism of the host against microbial infections, this discovery has profoundly influenced our understanding about the evolution of microbial pathogens. Notably, antigenic variation, the rapid acquisition of latency in the infected host, and acute immune suppression, are features of many persistent viral infections.

SELECTED PUBLICATIONS

  1. Pircher H,Moskophidis D, Rohrer U, Burki K, Hengartner H, Zinkernagel RM. (1990). Viral escape by selection of cytotoxic T cell -resistant virus variants in vivo. Nature. 346:629-633.            
  2. Aebische T,Moskophidis D, Rohrer UH, Zinkernagel RM, Hengartner H. (1991) In vitro selection of lymphocytic choriomeningitis virus escape mutants by cytotoxic T lymphocytes. Proc Natl Acad Sci USA. 88:11047-1151.
  3. Moskophidis D,Laine E, Zinkernagel RM. (1993). Peripheral clonal deletion of antiviral memory CD8+ T cells. Eur J Immunol.23: 3306-3311.
  4. Moskophidis D,Lechner F, Pircher H, Zinkernagel RM. (1993). Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 362:758-761.
  5. Moskophidis D,Lechner F, Hengartner H, Zinkernagel RM. (1994). MHC class I and MHC-linked capacity for generating an antiviral CTL response determines susceptibility to CTL exhaustion and establishment of virus persistence in mice. J Immunol.152: 4976-4983.
  6. Moskophidis D,Zinkernagel RM (1995). Immunobiology of cytotoxic T cell escape mutants of lymphocytic choriomeningitis. J Virol. 69: 2187-2193.
  7. Moskophidis D,Kioussis D. (1998). Contribution of virus-specific CD8+ cytotoxic T cells to virus clearance or pathologic manifestations of influenza virus infection in a T cell receptor transgenic mouse model. J Exp Med. 188:223-232.
  8. Huang L, NF Mivechi,D Moskophidis. (2001). Insights into regulation and function of the major stress-induced hsp70 molecular chaperone in vivo: Analysis of mice with targeted gene disruption of the hsp70.1 or hsp70.3 genes. Mol Cell Biol. 21:8575-8591.
  9. Zhou S, Ou R, Huang L, Price G,Moskophidis D. (2004). Differential tissue-specific regulation of CD8+ T cell mediated immune response during chronic viral infection. J Virol. 78:3578-3600.
  10. Min JN, Zhang Y,Moskophidis D,Mivechi NF. (2004). Unique contribution of heat shock factor 4 in ocular lens development and fiber cell differentiation. Genesis. 40:205-217.
  11. Huang L, Min JN, Masters S, Mivechi NF,Moskophidis D. (2007). Insights into function and regulation of small heat shock protein 25 (HSPB1) in a mouse model with targeted gene disruption. Genesis. 45:487-501.
  12. Jin X,Moskophidis D*,Mivechi NF*. (2011). Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Cell Metabolism. 14:91-103. (*corresponding authors)
  13. Xi C, Y., Hu, P. Buckhaults, Moskophidis, and N.F. Mivechi (2012). Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. J Biol. Chem. 287:35646-35657.
  14. Eroglu, B., M. Jin-Na, Y. Zhang, Szurek, E., Moskophidis, Ali Eroglu, and N.F. Mivechi. (2014). Genetic Interaction Between Heat Shock Transcription Factor Binding Protein 1 (HSBP1) and BRG1 Component of the Wnt Signaling Pathway During Early Embryonic Development. Dev. Biol. 386:448-460.
  15. Qiao, A., X. Jin, J. Pang, D. Moskophidis*, and Nahid F. Mivechi*. (2017). The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis Journal Cell Biology 216: 723-741 (*corresponding authors).
  16. Jin X, A. Qiao, D. Moskophidis, and N.F. Mivechi (2017). Alanine Substitution of Serine 303/307 Phosphorylation Motifs of Hsf1 Lowers the Threshold of Activation Leading to Obesity and Insulin Resistance in a Knock-In Mouse Model. Journal of Biol. Chem. (in press).

Research Team

Junfeng Pang, Ph.D.

Postdoctoral Fellow

JPANG@augusta.edu

Bhaumik Pandya

Graduate Student

BPANDYA@augusta.edu

Chao Jiang

Research Assistant

CJIANG@augusta.edu