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Scott Alper, PhD

Associate Professor of Immunology & Microbiology


 

 

1400 Jackson St., A640
Denver, CO 80045
Phone: 303-270-2659 Office, 303-270-2698 Lab
E-mail: alpers@njhealth.org

Dr. Alper's National Jewish Health webpage

Overview

The human immune response has both a rapid innate component and a slower but more specific adaptive component. The innate immune response involves the action of phagocytic and cytotoxic cells, which rapidly migrate to the site of infection and produce antimicrobial compounds. Innate immunity not only regulates the inflammatory response; it also plays a key role in the activation of adaptive immunity, which involves cells and immune mediators such as T cells, B cells, and antibodies. Thus, a robust innate immune response is critical for fighting infection.

Of course, too much of a good thing is not necessarily good. If the innate immune response becomes activated chronically, this can contribute to the pathogenesis of many different diseases with an inflammatory component. Thus it is critical not only that innate immunity is activated when needed (upon infection) but that this response is also self-limiting and ultimately inactivated when no longer needed.

Dr. Alper's laboratory is focused on understanding the regulation of the innate immune response, particularly as it relates to the basis for inflammatory disease. The signaling pathways involved in the activation of innate immunity have been studied by numerous labs. In contrast, the pathways that terminate this response are much less understood. The Alper laboratory is investigating two signaling mechanisms that terminate persistent inflammation and therefore prevent chronic inflammatory disease: the regulation of alternative splicing in the Toll-like receptor (TLR) signaling pathway, and the subcellular trafficking of TLR signaling pathway components. Understanding how the maintenance of TLR signaling is regulated offers the potential to devise ways to ensure that inflammation is limited—activated to fight infection but terminated to prevent diseases with an inflammatory component such as COPD, atherosclerosis, and cancer


Regulation of alternative pre-mRNA splicing in the TLR pathway to limit inflammation
One negative feedback loop that limits persistent TLR-induced inflammation is the production of negatively acting proteins specified by alternative mRNA splice forms of TLR pathway components. Production of these negative regulators (including a negatively acting isoform of the TLR adaptor MyD88) is induced by TLR stimulation, and thus production of these alternative splice forms constitutes a negative feedback loop to limit inflammation (see Figure).
Our studies suggest that genes in the TLR pathway are poised to undergo alternative splicing to terminate persistent inflammation. Thus, a significant focus in our laboratory is on investigating the mechanisms that mediate this important negative feedback loop. Using genetic, genomic, biochemical, and computational approaches, we have identified components of the TLR signaling pathway and components of the core pre-mRNA splicing machinery that mediate lipopolysaccharide (LPS)-induced alternative splicing in the TLR signaling pathway. These mechanistic studies are informing on a key fundamental biological question, how signal-induced alternative splicing is regulated.

We also are examining the effects of this alternative splicing in two models of diseases with an inflammatory component, acute respiratory distress syndrome (ARDS) and acute myeloid leukemia (AML). In our lung studies, we are using mouse models to determine the effect of alternative splicing on inflammatory lung disease. We also are testing if splicing in the TLR pathway is perturbed in patients with ARDS. For our leukemia studies, we are examining the effect of spliceosome mutations on inflammation and cancer pathogenesis. One factor known to influence the pathogenesis of leukemia is altered inflammatory signaling. A second factor implicated in leukemia pathogenesis is altered splicing; spliceosome genes are recurrently mutated at a high frequency in leukemia. Our discovery that these splicing factors regulate inflammation unifies the disparate observations on the roles of inflammation and mRNA splicing in the development of leukemia, suggesting that spliceosome mutations could enhance inflammation to affect disease.


Spatiotemporal regulation of TLR signaling by a novel RAB-GAP
Using mouse and macrophage models, we have identified Tbc1d23, a candidate RAB-GAP, as an inhibitor of the maintenance but not the initiation of TLR signaling. RABs are members of the RAS superfamily of small GTPases that mediate vesicle trafficking within the cell. RAB-GAPs inhibit their cognate RABs by facilitating the hydrolysis of the GTP on the RAB. Our studies demonstrate that Tbc1d23 likely acts by regulating a RAB and thus controls cellular trafficking to inhibit TLR signaling. We are currently investigating what RAB is regulated by Tbc1d23, what vesicles/proteins are trafficked by Tbc1d23, and how Tbc1d23 impacts the TLR signaling pathway. We also have identified other proteins that bind to Tbc1d23 and mediate its effects. Thus, we have discovered a new signaling pathway that controls the maintenance of TLR signaling several hours after challenge; this pathway regulates the canonical TLR pathway. Our expectation is that targeting this pathway pharmacologically will be a useful approach to prevent chronic inflammation and chronic inflammatory disease without abolishing the essential initial anti-pathogen response.


  • De Arras L, Yang IV, Lackford B, Riches DWH, Prekeris R, Freedman JH, Schwartz DA and Alper S. Spatiotemporal inhibition of innate immunity signaling by the Tbc1d23 RAB-GAP. J. Immunol. 188: 2905-13 (2012).
  • De Arras, L, Seng, A, Lackford, B, Keikhaee, MR, Bowerman, B, Freedman, JH, Schwartz, DA and Alper, S. An evolutionarily conserved innate immunity protein interaction network. J. Biol. Chem. 288: 1967-1978 (2013).
  • De Arras L and Alper S. Limiting of the innate immune response by SF3A-dependent control of MyD88 alternative mRNA splicing. PLOS Genetics 9(10):e1003855 (2013).
  • De Arras L, Laws R, Leach S, Pontis K, Freedman JH, Schwartz DA and Alper, S. Comparative genomics RNAi screen identifies Eftud2 as a novel regulator of innate immunity. Genetics 197: 485-496 (2014).
  • De Arras L, Guthrie BS and Alper S. Using RNAi-interference to investigate the innate immune response in mouse macrophages. J. Vis. Exp. 93:e51306 (2014). 
  • O’Connor BP, Danhorn T, De Arras L, Flatley BR, Marcus RA, Farias-Hesson E, Leach SM and Alper S. Regulation of Toll-like receptor signaling by the SF3a mRNA splicing complex. PLOS Genetics. 11(2):e1004932 (2015).
  • Alper S, Warg LA, De Arras L, Flatley BR, Davidson EJ, Adams J, Smith K, Wohlford-Lenane CL, McCray PB Jr, Pedersen BS, Schwartz DA and Yang IV. Novel Innate Immune Genes Regulating the Macrophage Response to Gram Positive Bacteria. Genetics. 204(1):327-36 (2016).
  • Blumhagen RZ, Hedin BR, Malcolm KC, Burnham EL, Moss M, Abraham E, Huie TJ, Nick JA, Fingerlin TE and Alper S. Alternative Pre-mRNA Splicing of Toll-Like Receptor Signaling Components in Peripheral Blood Mononuclear Cells from ARDS Patients. Am J Physiol Lung Cell Mol Physiol. 313(5):L930-L939 (2017).
  • Pollyea DA, Hedin DR, O’Connor BP and Alper S. Monocyte function in patients with Myelodysplastic Syndrome. J Leukoc Biol. 104(3):641-647 (2018).
  • Lee F and Alper S. Functional genomics in murine macrophages. Methods in Molecular Biology. 1809:289-298 (2018). 
  • Alper S and Janssen WJ., eds. Lung Innate Immunity and Inflammation: Methods and Protocols (Methods in Molecular Biology 1809). New York: Humana Press, 433 p. (2018).
  • Pollyea DA, Harris C, Rabe JL, Hedin BR, De Arras L, Katz S, Wheeler E, Bejar R, Walter MJ, Jordan CT, Pietras EM and Alper S. Myelodysplastic syndrome-associated spliceosome gene mutations enhance innate immune signaling. Haematologica. Epub ahead of print March 7, 2019.