Research Overview

 

RESEARCH OVERVIEW

 Transcriptional gene regulation is central to all biological processes and underlies many human diseases.  Dr. Liou investigates the roles of oncogenic transcription factors and signaling events in the onset of autoimmune disease, inflammation, and cancer. The goal of her research is to develop novel therapies by targeting disease-specific signaling molecules and oncogenic transcription factors.

 Role of Rel/NF-kB in inflammation and autoimmune disease

 Autoimmune diseases arise from hyperactive immune responses against self-antigens.  It is estimated that 5-8 percent of the human population is afflicted with one or more of the 80 types of autoimmune diseases, some of the most common ones are rheumatoid arthritis, type I diabetes, multiple sclerosis, inflammatory bowel disease, and lupus erythematosis.  Although the etiology of many autoimmune diseases is tissue-specific, recent evidence points toward common mechanisms leading to immune tolerance breakdown, in particular genetic mutations that lead to hyperactive autoreactive T cells and B cells.

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. 

 Role of persistent Rel/NF-kB activation in cancer cell survival and drug resistance

 Several members of the Rel/NF-kB family, including c-Rel, p52 (lyt10), and Bcl-3, were initially identified as oncogenes that are activated as a result of gene amplification or chromosomal translocation in human malignant B cells.  Persistent Rel/NF-kB activation has been subsequently observed in a wide range of hematopoietic tumors, viral-induced cancers, and solid tumors.  Dr. Liou has initially focused her research on the c-Rel proto-oncogene and its tumorigenic role in B cells.  Her team first demonstrated that c-Rel regulates normal mature B cell proliferation and survival via the regulation of cyclin E and E2F3a, as well as BclX, Bfl1, and Mcl1 expression.  Using microarray analyses they further identified novel c-Rel target genes including growth factors, cytokines, transcription factors, and signaling molecules. 

 Persistent Rel/NF-kB activation has been shown to confer drug resistance in B cell tumors.  Dr. Liou’s team is currently using small interference RNA (siRNA) technology and small molecular inhibitors of Rel/NF-kB to investigate the roles of Rel/NF-kB in tumor growth, survival, and drug resistance.  Through collaboration with clinical investigators and cancer researchers at the Weill Medical College of Cornell University, Dr. Liou’s translational research projects investigate the mechanisms and roles of persistent Rel/NF-kB activation in the survival and drug resistance using cell lines or patient samples derived from chronic lymphocytic leukemia, multiple myeloma, and diffuse large B cell lymphoma.  The goal of the translational research is to understand disease mechanism, identify novel therapeutic targets, and develop novel therapies by targeting Rel/NF-kB members.

 Development of Rel/NF-kB inhibitors as potential therapies for cancer and autoimmune disease

 

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)

FUNDING AGENCIES

National Cancer Institute

National Institute of Allergy and Infectious Diseases

National Institute of Mental Health

Leukemia & Lymphoma Society

Multiple Myeloma Research Foundation                      

Chronic Lymphocytic Leukemia Center 

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 America                     

Leukemia Research Foundation

Tolly Vinik Pilot Program

Leukemia Research Foundation

Dorothy Rodbell Cohen Foundation for Cancer Research

 

 

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