Postdoctoral Position focused on alternative splicing and immunity

Posted on December 2,

Scott Alper’s laboratoryat National Jewish Health in Denver, CO is recruiting Postdoctoral Fellows. The Alper lab is focused on understanding mechanisms that terminate pro-inflammatory signaling pathways. We have a particular interest in manipulating these signaling pathways to prevent persistent inflammation and chronic inflammatory disease while maintaining a robust host defense response. In this regard, we have discovered that alternative pre-mRNA splicing plays a key role in terminating persistent Toll-like Receptor (TLR) signaling. Current areas of focus in the lab include:

1. The effect of spliceosome mutations found in patients with Acute Myeloid Leukemia (AML) and related myeloid cancers. These somatically acquired spliceosome mutations are found in patients with AML and other blood cancers. These mutations induce substantial changes in gene expression and pre-mRNA splicing. Using mouse models engineered to express these mutations and human patient samples, we have demonstrated that these mutations are profoundly pro-inflammatory. We and others have hypothesized that inflammation is a contributing factor to myeloid malignancy development. We also have found that these cancer-associated mutations induce immunodeficiency in mouse models of the disease by perturbing host defense functions in myeloid cells. This may help explain the significant host defense defects in these patients, who are at risk of fatal infection. Current projects are focused on: (1) how these cancer-associated spliceosome mutations enhance inflammation, (2) how this enhanced inflammation drives leukemia development, and (3) how these mutations induce immunodeficiency in mice and humans.

2. Alternative pre-mRNA splicing as a mechanism that terminates persistent Toll-like Receptor (TLR) signaling to prevent disease. We are investigating how alternative pre-mRNA splicing prevents persistent TLR signaling; this mechanism may play a role in preventing chronic inflammatory disorders. Alternative pre-mRNA splicing converts positive regulators of TLR signaling to negative regulators that terminate the response. In a study of patient samples from individuals with Acute Respiratory Distress Syndrome (ARDS), a life-threatening lung-associated acute inflammatory disorder, we found that splicing of TLR signaling genes was perturbed and that these changes correlated with patient outcome. We have generated novel mouse models that allow us to investigate the effects of alternative splicing on ARDS and other inflammatory disorders.

National Jewish Health, a world-renowned clinical and research hospital focusing on lung and immune diseases, is in Denver, CO, located just a few miles east of downtown. The University of Colorado School of Medicine is just a few miles away from National Jewish Health.

To apply or enquire further, please contact:

Scott Alper, PhD
National Jewish Health Dept. of Immunology and Genomic Medicine
University of Colorado Denver Dept. of Immunology and Microbiology
[email protected]