Dr. Liou and her team have shown that the Rel/NF-kB family of transcription factors (TF), in particular c-Rel, plays a critical role in lymphocyte clonal expansion and inflammatory autoimmune pathogenesis. By generating the c-Rel knockout mice, they first demonstrated that blocking c-Rel activity prevents animals from developing allergic lung inflammation (asthma), autoimmune diseases (multiple sclerosis, rheumatoid arthritis, type I diabetes), and transplant rejection. The underlying mechanism mediated by c-Rel is attributed to its critical function in regulating the expression of inflammatory cytokines (e.g. IL-2, IL-6, TNF, IFN-g, IL-12, IL-23, IL-27), T and B lymphocyte cell cycle regulators and cell survival proteins. These studies have provided first proof-of-concept that c-Rel is an exciting therapeutic target for inflammation, autoimmune diseases, and transplantation rejection.
Dr. Liou’s previous studies using knockout mice and RNA silencing approaches have provided compelling proof-of-concept that Rel/NF-kB is a valid therapeutic target for inflammation, autoimmune diseases, transplantation rejection, and B cell tumors. Her team has initiated a drug discovery program with the goal to develop Rel/NF-kB inhibitors as potential novel therapies for cancer and autoimmune disease.
Several approaches are currently underway. (I) High throughput screening (HTS) assays have been developed to identify small molecular inhibitors of Rel/NF-kB transcription factors. Her team is currently evaluating several compounds using biochemical and cellular based assays. (II) Using the approach of small molecular microarray, Dr. Liou and her collaborators are evaluating the inhibitory activity of several dozens of molecules directly bind with c-Rel. (III) By using c-Rel target gene signature, her team has identified candidate Rel/NF-kB signaling inhibitors from a pool of FDA approved drugs and bioactive molecules. (IV) Dr. Liou also investigates potential application of Rel/NF-kB member specific siRNAs as therapeutic agents.
It is conceivable that these inhibitors and small molecules have the potential to be used as biological tools to investigate the mechanisms of autoimmunity and tumorigenesis, as well as to be developed into therapeutics for cancer and autoimmune diseases. For autoimmune diseases, the inhibitors will be evaluated for therapeutic potential in dampening organ-specific and systemic inflammation, as well as for inducing antigen-specific immune tolerance. For cancer research, the Rel/NF-kB inhibitors will be evaluated for therapeutic potential to target tumors with persistent Rel/NF-kB that are refractory to conventional therapies, as well to be used as tools to identify specific signaling alterations that lead to sustained Rel/NF-kB in the first place.
ONGOING RESEARCH PROJECTS
· Development of high throughput screening assays to identify novel Rel/NF-kB inhibitors
· Evaluate c-Rel binding compounds, FDA approved drugs, and bioactive molecules as potential Rel/NF-kB inhibitors
· Using Rel/NF-kB inhibitors, siRNAs, and knockout mice to investigate the role of Rel/NF-kB in autoimmune diseases
· Using Rel/NF-kB inhibitors, siRNAs, and knockout mice to investigate the role of Rel/NF-kB in cancer cell survival and drug resistance
· Using Rel/NF-kB inhibitors, siRNAs, and knockout mice to investigate the role of Rel/NF-kB in aging and longevity
· Investigate and evaluate Rel/NF-kB inhibitors as potential therapy for autoimmune diseases (rheumatoid arthritis, multiple sclerosis, type 1 diabetes, inflammatory bowel disease)
· Investigate and evaluate Rel/NF-kB inhibitors as potential therapy for B cell tumors (chronic lymphocytic leukemia, multiple myeloma, diffuse large B cell lymphoma)
National Cancer Institute
National Institute of Mental Health
Leukemia & Lymphoma Society
Multiple Myeloma Research Foundation
American Cancer Society--Junior Faculty Award
March of Dimes-Basil O'Connor Starter Scholar Award
Irma Hirschl/Monique Weill-Caulier Career Scientist Awards
Charles Offin Charitable Trust Award
Cancer Research Foundation of
Leukemia Research Foundation
Tolly Vinik Pilot Program
Leukemia Research Foundation
Dorothy Rodbell Cohen Foundation for Cancer Research