Caleb B. Kallen, MD, PhD
Philadelphia, PA 19107
(215) 955-5577 fax
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
Most Recent Peer-Reviewed Publications
- Obesity-induced endoplasmic reticulum stress causes lung endothelial dysfunction and promotes acute lung injury
- Obesity-induced adipokine imbalance impairs mouse pulmonary vascular endothelial function and primes the lung for injury
- Direct effects of leptin and adiponectin on peripheral reproductive tissues: A critical review
- A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis
- Chronic alcohol ingestion in rats alters lung metabolism, promotes lipid accumulation, and impairs alveolar macrophage functions
- MRNA-binding protein TIA-1 reduces cytokine expression in human endometrial stromal cells and is down-regulated in ectopic endometrium
- 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
- Therapeutic approaches: Lifestyle, exercise, and medications
- Osteoporosis: Who gets it and how do you know?
- Diagnosing secondary causes of osteoporosis
- Osteoporosis: After treatment, you need to monitor
- 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
- Endocrine Disorders and Infertility
- The mRNA-binding protein HuR is regulated in the menstrual cycle and repressed in ectopic endometrium
- The tri-nucleotide spacer sequence between estrogen response element half-sites is conserved and modulates ERα-mediated transcriptional responses
- Location analysis for the estrogen receptor-α reveals binding to diverse ERE sequences and widespread binding within repetitive DNA elements