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We will utilize HIV gene expression as a model of gene expression and define signals that allow RNA polymerase II activity (closely spaced polymerases, termed convoys) using noise inducing signals. Noise in gene expression often results from promoter transitions between on and off states that generate episodic ‘bursts’ of transcription. In a ‘two-state’ model, RNA polymerase II stalls on the HIV Long Terminal Repeat (LTR) promoter but when the elongation stall is relieved, multiple polymerases can read through resulting in a burst of transcripts and highly variable expression levels. We will therefore perform calculations of the noise strength equation and stochastic kinetic constants using HIV promoter basal activity as well as mathematical modeling of HIV’s super activator Tat protein for a positive-feedback circuitry that enables persistence and strongly controls latency.
We will use experimental data that created noise on HIV promoter in both T-cells and macrophages (both with very different transcriptional kinetics). The noise inducers will include exosomes from normal cells, low level irradiation, and epigenetic activators on HIV promoter. We will define how the RNA polymerase II activity is altered using various noise inducers and whether signals that block noise induction will suppress HIV promoter into a permanent state of dormancy and latency.
Fatah Kashanchi, Ph.D. has been working on virus research for more than 20 years. During his tenure at NIH (intramural program) from 2000-2009, he published 31 papers and obtained more than $2.4 M of independent funding from private foundations for his research on human retroviruses. Since his departure from NIH, he has obtained more than $15.3 M in funding (NIH, DOD, DOE, and Keck). He has published seven book chapters and 196 peer-reviewed manuscripts (h index = 53), and served as an editorial board and reviewer for Retrovirology, JBC, J. Virol, Virology, NAR, MCB, 4 PLoS Journals, Cell, Molecular Cell, Nature Medicine, and Science Translational Medicine. He is a regular NIH study section member and has officially served on 141 panels since 2000 as chair and co-chair (27). Dr. Kashanchi has proven leadership quality as a key member of writing, developing and implementing the Washington DC-CFAR program that is currently being run at GWUMC. He also ran the scientific program at the NCBID/BRL at GMU for the first three years by hiring and mentoring Kylene Kehn-Hall (a former student), Aarthi Narayanan (former postdoc) and Ramin Hakami (a new hire from USMRMC). All were hired as tenure-track assistant professors.