Caleb B. Kallen, MD, PhD
Philadelphia, PA 19107
(215) 955-5577 fax
Most Recent Peer-reviewed Publications
- MRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells
- Estrogen targets fat mass and glucose metabolism by acting in the brain
- The mRNA-binding protein Zfp36 Is upregulated by β-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes
- β-Catenin independent cross-control between the estradiol and Wnt pathways in osteoblasts
- Intercalation of XR5944 with the estrogen response element is modulated by the tri-nucleotide spacer sequence between half-sites
Research and Clinical Interests
Our lab is investigating the role of mRNA-binding proteins in obesity-related inflammatory processes with a focus on insulin sensitivity and atherosclerosis.
Obesity is a state of chronic, low-grade inflammation. This inflammation contributes to obesity-associated disorders including atherosclerosis and diabetes. An essential means of regulating inflammatory cytokine gene expression occurs at the level of mRNA stability. Much of this regulation occurs by the binding and stabilizing, or destabilizing, of target mRNAs by proteins that recognize AU-rich Elements located in the untranslated regions of these transcripts.
Zinc Finger Protein 36 (ZFP36) is an ARE-binding protein (ARE-BP) that destabilizes target mRNAs leading to message destruction and diminished protein expression. Expressed in a variety of cell types including monocytes, macrophages, adipocytes, and vascular endothelial cells, ZFP36 targets important mRNA transcripts including Tumor Necrosis Factor-Î±, Granulocyte Macrophage Colony-Stimulating Factor, IL-3, IL-6, IL-8, Vascular Endothelial Growth Factor, and cyclooxygenase-2. ZFP36 null mice demonstrate cachexia, arthritis, and auto-immunity, indicating that ZFP36 subserves important and non-redundant functions. Recently, ZFP36 was demonstrated to interact with the p65 subunit of Nuclear factor-ÎºB (NF-ÎºB), leading to decreased nuclear import and diminished transcriptional activation mediated by NF-ÎºB. These data suggest two important mechanisms by which ZFP36 might suppress inflammatory responses: by regulating NF-ÎºB-mediated transcriptional responses and by regulating cytokine mRNA stability.
Our lab is investigating the role ZFP36 in obesity-related inflammatory processes with a focus on insulin sensitivity and atherosclerosis. We plan to measure the effects of high and low ZFP36 expression, in vivo and in vitro, in two important cell types: adipocytes (fat cells) and macrophages. We hypothesize that high ZFP36 expression will reduce inflammation in adipocytes and macrophages. We will test whether high ZFP36 expression in adipocytes and macrophages decreases inflammation in obese mice and protects against insulin resistance and atherosclerosis. These studies will provide proof-of-principle that ZFP36 might one day be exploited to treat important human disorders including atherosclerosis, endometriosis, and some cancers, all of which share inflammation as a pathogenic precursor.
Collaborative projects explore the functions of ZFP36 and alternative ARE-BPs in diverse processes including endometriosis, reproduction, liver regeneration, and cachexia