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.
Dr. Hassel is a member of the Tumor Immunology and Immunotherapy Program within the University of Maryland Marlene and Stewart Greenebaum Cancer Center (UMGCC) Program in Oncology, and is an Associate Professor of Microbiology and Immunology. Dr. Hassel's research focuses on the endoribonuclease RNase-L, a component of the innate immune response that mediates tumor suppressor activities. His studies described below have revealed novel roles for RNase-L in which it acts to attenuate inflammatory and proliferative responses thereby contributing to tumor suppressor and host defense activities. With the goal of developing RNase-L-targeted agents for diagnostic and therapeutic applications in cancer and immune disorders, Dr. Hassel actively collaborates with basic and clinical UMGCC investigators.
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 an unchecked 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.
Training and outreach activities in the Hassel lab.
In addition to my research activities as a PI and laboratory mentor, I serve in multiple and diverse training, education and outreach capacities. 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, I give presentations at local high schools on Cancer and Career Paths in Biomedical Science. As Faculty-Scholar Liaison for the UM,B Continuing Umbrella of Research Experience Scholars (CURES) program awarded to the UMGCC by the NCI, I help establish a middle school through college pipeline of mentoring and exposure to biomedical science. I have directed the Greenebaum Cancer Center/Nathan Schnaper Summer Intern Program in cancer research for undergraduate students since 2001 (http://www.umgcc.org/research/summer_internships.htm). In the 2015 academic year I will take the position of Director of the Molecular Microbiology and Immunology graduate program. I currently teach in several graduate and medical school courses and was named Teacher of the Year in 2013. I serve additional training roles as co-investigator on the Signaling Pathways in Innate Immunity T32 training grant as a member of the Baltimore Albert Schweitzer Fellowship Advisory Board in which I help administer outreach projects designed and implemented by professional school students. Through these roles, I have the privilege of interacting with trainees at all levels of biomedical education. The presence of this continuum of research experience in my lab creates a rich and dynamic environment and provides me with a perspective that facilitates effective mentoring of aspiring scientists and physicians.