As a researcher, my major commitment is to investigate cellular proliferation and transformation, and molecular and chemical genetics of the integrated endoplasmic reticulum stress response (IERSR).
Cellular proliferation and transformation. Origins of this research lay in my discovery that Cyclin D1 and p27Kip1 link Ras signaling to cell cycle machinery. Ras, activated in 15-20% of human cancers, interacts with translation initiation factors in a feed-forward loop to increase expression of oncogenic proteins at the level of translation. The realization that translation initiation is at the apex of many oncogenic pathways prompted me to test the hypothesis that translation initiation factors can be targeted for cancer therapy.
My collaborators and I have identified several small molecule translation initiation inhibitors using high throughput assays. These include diaryl-oxindoles, thiozolidones, and N,N’-diarylureas that inhibit eIF2.GTP.met-tRNAi ternary and thiozolidonehydrozone-based agents that inhibit eIF4F translation initiation complex. I also developed assays to accredit the in vivo mechanism of action and the specificity of these agents. In the course of these studies I identified heme regulated inhibitor kinase as a novel target for cancer therapy. These studies are currently supported by an RO1 and an industry grant on which I am the Principal Investigator.
Molecular and chemical genetics of the IERSR. The IERSR maintains a balance between demand and capacity for folding newly synthesized proteins. Defects of the IERSR are associated with multiple human disorders, including cancer, and neuro-degeneration. That the eIF2.GTP.met-tRNAi is a critical component of the IERSR prompted me to study the molecular and chemical genetics of the IERSR. My group utilized high throughput assays to screen whole-genome human siRNA and small molecule libraries and identified unique genetic and chemical modifiers of the IERSR. I will capitalize on these probes to study biology of endoplasmic reticulum and delineate the role of IERSR in the pathobiology of human disorders, particularly cancer. In collaboration with leading experts, I will attempt to delineate the role of the IERSR in the pathobiology of the motor-neuron diseases. Both RO1 and R21 grant applications to support these work are at various stages of review process.