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Research
Molecular mechanisms of chronic inflammation regulation
Inflammation produced in response to microbial infection and tissue damage is critical to protect against infections across the board and organize long-term adaptive immunity against specific pathogens. Chronic and uncontrolled inflammation, on the other hand, typically causes major tissue damage and significant pathogenicity due to overactive immune responses. Shembade’s laboratory focuses on understanding the molecular mechanisms of chronic inflammation regulation in cancer cells, as well as inflammatory diseases and innate immune receptor stimulation.
Molecular mechanisms of NF-κB regulation in EBV, KSHV, and HTLV-infected cells
Chronic inflammation induced by NF-κB is essential for the survival of leukemia and lymphoma cells infected with oncogenic viruses, such as EBV, KSHV, and HTLV-1. Viral oncogenes, LMP-1 of EBV, vFLIP and vGPCR of KSHV, and Tax of HTLV-1, are hijacking and post-translationally modifying host factors to maintain chronic NF-κB activation in leukemias and lymphomas. However, the host factors that are post-translationally modified are not fully known. Thus, another focus of his laboratory is to identify the mechanisms and host factors that post-translationally modified by the viral oncogenes to maintain chronic NF-κB activation in leukemias and lymphomas.
Regulation of translation initiation during KSHV replication and oncogenesis
Despite advances in our understanding of KSHV pathogenesis and the implementation of rationally designed therapies based on these findings, advanced KS is largely incurable, and many of the most promising new therapies continue to face major roadblocks and implementation issues in the context of ART. KSHV regulate the oxygen sensing machinery allowed the virus to adjust the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 alternative cap-binding. This was essential for KSHV replication. investigate how KSHV regulation of the oxygen sensing mechanism (O2SM), which leads to HIF2a activation of translational initiation via eIF4EH, contributes to KSHV replication and innate immunity evasion; and 2) investigate how KSHV regulation of eIF4EH contributes to KSHV replication and innate immunity evasion. 2: Investigate how KSHV modulation of the oxygen sensing machinery, which results in HIF2a stimulation of translational initiation by eIF4EH, contributes to KSHV oncogenesis in mouse and human MSCs. 3: The role of translation initiation plasticity in PDGFRA targeted therapy resistance.
Develop a KSHV oncogenesis mouse model in the HIV/AIDS setting
Pathogenesis-based treatment design and testing is hampered by a lack of adequate HIV/AIDS-specific KSHV oncogenesis models. In collaboration with the Dr. Roy Lab, we discovered that a) EcoHIV therapy of mECK36 (Bac36KSHV-infected) tumor-bearing nude mice promotes tumor cell proliferation, and b) EcoHIV infection of Balb/c mice allows grafting and growth of KSHV tumors. Thus, we want to know if "new in vitro and in vivo models of HIV/AIDS-associated malignancies can be developed to study their development, pathogenesis, and the potential evaluation of novel treatments for common HIV/AIDS-associated malignancies."
Regulation of type I and II interferons signaling
Type I interferons (IFN-α and IFN-β) and type II interferon (IFN-γ) are induced in response to infections with viruses or bacteria. IFNs bind to their cognate receptor, which plays important roles in host defense against invading pathogens. Type I interferons provide protection against many viral infections, whereas type II interferon is essential for host defense against some bacterial and parasitic pathogens. Interestingly, numerous studies have also found that functional dysregulation of either interferon response can lead to chronic pathological conditions associated with numerous human diseases, including tissue damage and autoimmunity. Type I and II IFN signaling pathways are dysregulated in oncogenic virus-infected cells to maintain chronic inflammation condition, initiate, and develop tumors. However, the molecular mechanisms and the host factors that are involved in regulating interferon receptors are poorly understood. The overall objective of this proposal is to determine the molecular mechanisms of action of a host protein, P-2 (also known as MPEG-1), on Type I and II IFN signaling pathways and oncogenic virus-infected cells.