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Bret A. Hassel, PhD

Academic Title:

Associate Professor

Primary Appointment:

Microbiology and Immunology

Additional Title:

Director, Graduate Program in Molecular Microbiology and Immunology; Director, Nathan Schnaper Intern Program in Translational Cancer Research; Financial Sustainability Co-Chair, UMB CURE Scholars Program

Location:

Howard Hall, 348

Phone (Primary):

410-328-2344

Phone (Secondary):

443-850-5239

Education and Training

Dr. Hassel received his B.S. from the University of Miami and his Ph.D. from the Johns Hopkins University in 1989. Following postdoctoral fellowships at the Uniformed Services University of the Health Sciences and the Cleveland Clinic Foundation, Dr. Hassel joined the faculty of the Department of Microbiology and Immunology at the University of Maryland, School of Medicine in 1995.

Biosketch

Research in my laboratory focuses on the endonuclease RNase-L that functions in host defense from microbial pathogens and as an endogenous constraint on cell proliferation. I and co-workers were the first to clone RNase-L over 20 years ago and subsequent work from my lab has contributed significantly to our current understanding of its biochemical and biological activities. The long-term goal of my work is to determine the mechanisms by which RNase-L mediates innate immune and tumor suppressor functions with the objective of modulating these activities for therapeutic applications.

In addition to my research activities as a PI and laboratory mentor, I serve in multiple training, education and outreach capacities as central components of my professional activities. I am Director of the Molecular Microbiology and Immunology graduate program, have taught in nine graduate and medical school courses and was named Teacher of the Year in 2013. I have served on the thesis committees of over 60 students and directly mentored 33 postdoctoral, graduate and undergraduate trainees. I am PI of the undergraduate Nathan Schnaper Intern Program in Translational Cancer Research and Co-Chair of Funding and Sustainability for the NCI-funded UMB Continuing Umbrella of Research Experience (CURE) minority STEM education pipeline. I serve additional training roles as co-PI and investigator on the NIGMS-funded minority Science Training for Advancing Biomedical Research Post-baccalaureate Research and Education Program and the NIAID Signaling Pathways in Innate Immunity T32 training grant. My educational activities have emphasized diversity enhancement through service on minority-focused training programs including BUILD/ASCEND and MBRS RISE at Morgan State University, Pre-Marc-U-STARs and Meyerhoff Scholars at UMBC and Bridges to the Doctorate with Towson University

Also see link to full Biosketch

Research/Clinical Keywords

Rnase-L, type-1 interferon, mRNA turnover, innate immunity, tumor suppressor

Highlighted Publications

Publications

  1. Ezelle, H.J. and Hassel, B.A. 2011. Pathologic effects of RNase-L dysregulation in immunity and proliferative control. Frontiers in Bioscience 4:767-86. PMCID: PMC3468953.
  2. Li, X.L., Ezelle, H.J., Kang, T-J., Zhang, L., Shirey, K., Harro, J., Hasday, J.D. Mohapatra, S.K., Crasta, O., Vogel, S.N., Cross, A.S., and Hassel, B.A. 2008 An essential role for the antiviral endoribonuclease, RNase-L, in antibacterial immunity. PNAS 105:20816 PMCID: PMC2648959.
  3. Brennan-Laun SE, Li XL, Ezelle HJ, Venkataraman T, Blackshear PJ, Wilson GM, Hassel B.A. 2014 RNase L Attenuates Mitogen-stimulated Gene Expression via Transcriptional and Post-Transcriptional Mechanisms to Limit the Proliferative Response. J Biol Chem. 2014 289:33629-43. PMCID: PMC4246114.
  4. Long TM, Nisa S, Donnenberg MS, Hassel B.A. 2014 Enteropathogenic Escherichia coli inhibits type I interferon- and RNase-L-mediated host defense to disrupt intestinal epithelial cell barrier function. Infect Immun. 82:2802-14. PMCID: PMC4097611.
  5. Krishnamurthy, M, Adnan Siddiqui, M, Dayal, S, Naji, M, Ezelle, HJ, Zeng, C, Zhou, A, Hassel, B.A. 2014 RNase L interacts with Filamin A to regulate actin dynamics and barrier function for viral entry. MBio. 5:e02012; PMCID: PMC4217177.

Additional Publication Citations

  1. Ezelle, H.J. and Hassel, B.A. 2011. Pathologic effects of RNase-L dysregulation in immunity and proliferative control. Frontiers in Bioscience 4:767-86. PMCID: PMC3468953.
  2. Ezelle, HJ, Laun, SE, and Hassel, BA. The Roles of RNase-L in antimicrobial immunity and the cytoskeleton-associated innate response. Int J Mol Sci. 2016 8:1. PMID: 26760998
  3. Laun, S. and Hassel, B.A. 2014. RNase-L control of cellular mRNAs: roles in biologic functions and mechanisms of substrate targeting. Journal of Interferon and Cytokine Research 34:275-88. PMCID: PMC3976596.
  4. Zhou, A., Hassel, B.A.*and Silverman, R.H. Expression cloning of 2-5A-dependent RNase:  a uniquely regulated mediator of interferon action. Cell, 72:753-765. 1993. *shared first authorship.
  5. Hassel, B.A., Zhou, A., Sotomayor, C. Maran, A. and Silverman, R.H. A dominant negative mutant of 2-5A-dependent RNase suppresses antiproliferative and antiviral effects of interferon, EMBO J., 12:3297-3304. 1993.
  6. Castelli, J.C., Hassel, B.A., Wood, K.A., Li, X-L., Amemiyz, K., Dalakas, M.C., Torrence, P.F. and Youle, R.J.  A study of the interferon antiviral mechanism: apoptosis activation by the 2-5A system. J. Ex. Med., 186:1-6. 1997.
  7. Andersen, J.B., Li, X.-L., Judge, C.S., Zhou A., Jha, B.K., Shelby, S., Zhou, L., Silverman, R.H., and Hassel B.A. 2006 Role of 2-5A-dependent RNase-Lin senescence and longevity. Oncogene 26:3081-8.
  8. Andersen, JB, Mazan-Mamczarz K, Zhan M, Gorospe, M, and Hassel, B.A. 2009 Ribosomal protein mRNAs are primary targets of regulation in RNase-L-induced senescence. RNA Biology 6:3 1-11 PMCID: PMC2752476.
  9. Long T.M., Chakrabarti A., Ezelle H.J., Brennan S., Raufman J-P,Polyakova I., Silverman R.H., Hassel B.A. 2013 RNase-L deficiency exacerbates experimental colitis and colitis-associated cancer. Inflammatory Bowel Disease 196:1295-1305. PMCID: PMC3703736.

Research Interests

A regulated response to infection and injury is essential for host health and viability. Our cells and tissues are exposed to exogenous and endogenous ‘threats’ such as microbial pathogens and malignant cancers that can disrupt physiologic functions, resulting in pathogenesis and disease. The host response to these challenges must be rapidly induced to prevent sustained damage. Equally important is the efficient attenuation of these responses that is required to restore homeostasis. Indeed, impaired resolution of a host-threat response is associated with severe pathologic disorders. For example, inflammation can lead to chronic immune dysfunction if left unabated and unchecked proliferation in response to tissue damage can result in fibrosis and tumorigenesis. Understanding the molecular basis of the host response to such threats will thus reveal novel approaches to treat diseases in which this response is dysregulated such as immune disorders and cancer. Post-transcriptional regulation of mRNA turnover provides a means to rapidly reprogram gene expression that is an essential component of an effective host-threat response. Research in my laboratory focuses on the endonuclease RNase-L that functions in host defense from microbial pathogens, and as an endogenous constraint on cell proliferation, via the cleavage of RNA to post-transcriptionally regulate gene expression (1,2). The long term goal of my work is to determine the mechanisms by which RNase-L mediates its biologic functions and to modulate its activity for therapeutic applications.

RNase-L as an endogenous constraint on cell proliferation. RNase-L was originally discovered as a key mediator of type I interferon-induced antiviral activity and is now known to mediate a broader profile of important biologic activities (1,2). I and co-workers were the first to clone RNase-L over 20 years ago (3) and subsequent work from my lab has contributed significantly to our current understanding of its biological functions and mechanisms of action. For example, we identified antiproliferative (4), pro-apoptotic (5) and pro-senescence (6) activities of RNase-L that contribute to its antiviral and tumor suppressor functions. To dissect the mechanism by which RNase-L elicits these activities, my lab and others identified RNAs that are regulated by RNase-L (2,7,8). This work revealed that RNase-L regulates distinct profiles of RNAs in different biologic conditions and suggested that understanding how RNase-L selectively targets specific RNAs may provide an approach to modulate its activity. Towards this goal, our recent work demonstrated that RNase-L interacts with tristetraprolin (TTP), an RNA-binding protein (RNAbp) that binds A-U-rich element (ARE)-containing mRNAs to initiate their degradation (2). We hypothesize that TTP, and potentially other RNAbps, direct RNase-L cleavage to specific RNAs as part of a post-transcriptional regulatory network. Consistent with this model, we identified a subset of mRNAs that are regulated by RNase-L and TTP. We determined that RNase-L- and TTP-dependent downregulation of serum-response-factor (SRF) mRNA is an important mechanism by which the proliferative response is attenuated in mitogen-stimulated cells (9). Current research is focused on validating additional RNase-L/TTP-regulated transcripts and assessing the biologic consequenses of this regulation in specific physiologic and pathologic settings.

RNase-L in the host response to microbial pathogens. Although it has been historically studied as a host antiviral effector, our recent work has identified a novel role for RNase-L in antibacterial immunity. RNase-L deficiency led to a dysregulated innate immune response and increased mortality following intraperitoneal infection models (7) and in response to intestinal microbes released upon gastrointestinal (GI) injury in mouse models of colitis and colitis-associated cancer (10). Consistent with the role for RNase-L in GI homeostasis and defense from enteric pathogens suggested by these studies, RNase-L conferred protection from enteropathogenic Escherichia coli (EPEC)-induced barrier disruption in intestinal epithelial cells (11). To dissect the mechanism(s) by which RNase-L functions in host-microbe interactions, our recent study identified interacting proteins that suggested a new function for RNase-L in the cytoskeletal-tight junction protein network. RNase-L reduced virus entry and restricted intestinal epithelial cell permeability to bacterial pathogens supporting a role in barrier function. Remarkably, the cytoskeleton-associated barrier function of RNase-L occurred independent of the catalytic activity that is required for its signaling/effector functions (12). Based on these findings, we hypothesize that RNase-L plays dynamic structural and catalytic roles in host defense to link pathogen-induced cytoskeletal perturbations with activation of the innate immune response. Ongoing studies are aimed at identifying key RNase-L-cytoskeletal interactions and determining the role that pathogen-induced disruption of these contacts plays in initiating innate immune signaling through RNase-L. This information may reveal novel approaches for broad-spectrum antimicrobial therapies and treatment of disorders associated with barrier dysfunction.

Awards and Affiliations

2012    Editorial Board member, The Journal of Interferon and Cytokine Research

2013    Teacher of the Year, Graduate Program in Life Sciences

2014    NIH Immunology Fellowship Study Section (ZRG1 F07) and AREA ZRG IMM study sections

2015    Invited Reviewer, Welcome Trust PhD Training Grants

2015    Clark Lectureship, York College of Pennsylvania

2016    PROMISE AGEP Maryland Transformation Faculty Diversity Award

2016    Board of Advisors, NSF Scholarship in STEM Grant to Howard Community College

2016    International Cancer Education Conference Planning committee, Bethesda, MD

2016    Invited participant NCI Cancer Education Workshop, Bethesda MD

2016    NIH Study Section Special Emphasis Panel/Scientific Review Group 2017/01 ZRG1 F09B-M

2016    Invited Speaker Coppin State University Science Symposium

Grants and Contracts

see Biosketch link

Community Service

In addition to my roles with the UMB CURE, Nathan Schnaper Intern Program and local undergraduate programs described in my Biosketch, I give presentations at local high schools on Cancer and Career Paths in Biomedical Science in conjunction with the Achievement Counts program of the Maryland Business Roundtable for Education and the After School Science Fair program at the Maryland Science Center.

Professional Activity

see Biosketch link

Links of Interest

Molecular Microbiology and Immunology Graduate Program: http://lifesciences.umaryland.edu/microbiology/

UMB CURE Scholars Program:www.umbcure.org

Nathan Schnaper Intern Program: www.umm.edu/nsip