Siddharth Balachandran, PhD
Office Phone: 215-214-1527
Lab Phone: 215-214-1528
Molecular Regulation of NecroptosisRoshan Thapa, Shoko Nogusa & Rachelle Kosoff
Projects are focused on understanding how FADD and caspases prevent activation of RIP1 and RIP3, and how these negative regulators are disabled during an innate-immune response to license necrotptotic death. Collaborative studies with the Douglas Green (St. Jude Children’s Hospital) and Edward Mocarski (Emory University) labs are underway to determine the role mechanism by which RIP1 loss permits IFN-activated RIP3-driven cell death, and the contribution of IFNs to the perinatal lethality phenotype of RIP1-deficient animals.
Role of Necroptosis in Control of RNA VirusesShoko Nogusa & Rachelle Kosoff
We have identified an essential role for RIP3 in controlling acute infection by distinct classes of RNA viruses, including influenza A and the neurotropic rhabdovirus Vesicular Stomatitis Virus (VSV). Current projects seek to understand how RNA viruses RIP3, and how RIP3 then transduces parallel downstream necrotic and apoptotic cell death signals via, respectively, MLKL and caspases. Also of interest are the cell types in vivo that die by RIP3-dependent mechanisms. These projects are very collaborative and involve the combined expertise of the Green and Mocarski labs, as well as those of Paul Thomas (St. Jude Children’s Hospital) and Andrew Oberst (U. Washington). Ancillary projects examining the role of neuronal RIP3 in control of neurotropic viruses (VSV, measles virus) are also being pursued in collaboration with the Glenn Rall lab (Fox Chase).
Exploitation of Necroptosis for Treatment of Human MalignanciesRoshan Thapa
Our identification of RIP1/3-kinase-dependent necroptosis as an IFN-activated cell death mechanism, as well as our discovery of N-κB as a targetable survival factor that protects against IFN-induced necroptosis, may now allow the combinatorial use of NF-κB inhibitors (such as proteasome blockers) with IFNs for treatment of human malignancies. Projects are in place to determine how NF-κB protects cells from IFNs, and to test additional rational IFN-based combinations (e.g., IFN + SMAC-mimetics) for induction of cell death in tumor cells. Highlighting the translational potential of these studies, a phase I/II clinical trial employing IFN-α plus the proteasome inhibitor MLN9708 for advanced kidney cancer is underway at Fox Chase, based in large part on the lab’s discoveries. Additional collaborations are in place with the Testa lab at Fox Chase and the Degterev lab at Tufts that will develop and deploying new RIP1/3 kinase inhibitors for the prevention and treatment of asbestos-induced malignant mesothelioma.Top