• Current Projects

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    The role of the nuclear receptor peroxisome proliferator activated receptor-gamma (PPAR gamma) as a potential target to alter the sepsis-induced inflammatory response. PPAR gamma is a nuclear receptor with effects on lipid and glucose metabolism, atherosclerosis and inflammation. The thiazolidinediones (TZDs), pioglitazone and rosiglitazone, are Food and Drug Administration (FDA)-approved medications that activate PPAR gamma. TZDs are used therapeutically as insulin-sensitizers for patients with type 2 diabetes. In these patients TZDs have favorable effects on modulating the inflammatory response.

    The Kaplan laboratory is collaborating with Basilia Zingarelli, MD, PhD to investigate the critical molecular mechanisms involved in the PPAR gamma pathway in sepsis.

    Role of PPARgamma in Sepsis.

    Upon ligand binding, PPARg forms a heterodimer with the retinoic acid receptor (RXR). The interaction with the RXR allows the recruitment of a set of cofactors. This complex binds to the PPAR response element (PPRE) in the promoter region of certain target genes to modulate transcription.

    A second focus of the laboratory is on the increased susceptibility of diet-induced obesity to sepsis. The Kaplan laboratory focuses on the critical links between the inflammatory pathways in sepsis and obesity and the importance of adipose tissue biology on inflammation.

    Representative image of magnetic imaging with 7T MRI demonstrating that mice on a high fat diet have increased adiposity.

    Representative image of magnetic imaging with 7T MRI demonstrating that mice on a high fat diet have increased adiposity.

    Immunohistochemistry of F4/80 macrophage stain of liver sections of normal (A) and high fat (B) chow-fed mice demonstrating hepatic macrophage accumulation. 10x magnification.

    Immunohistochemistry of F4/80 macrophage stain of liver sections of normal (A) and high fat (B) chow-fed mice demonstrating hepatic macrophage accumulation. 10x magnification.

    The Kaplan laboratory is conducting a Phase 1 clinical trial to evaluate the pharmacokinetic characteristics, safety profile, and effect on inflammatory markers of pioglitazone in patients with severe sepsis and septic shock. Pioglitazone belongs to a class of drugs called thiazolidinediones (TZDs), which are commonly used in patients with type 2 diabetes. The preclinical work was initiated by Basilia Zingarelli, MD, PhD and in collaboration with Dr. Zingarelli the Kaplan laboratory continues to investigate the critical molecular mechanisms involved in the anti-inflammatory effects of TZDs in sepsis. The Pioglitazone in Pediatric Sepsis study is a collaborative effort with Hector Wong, MD (Director, Division of Critical Care Medicine), Alexander Vinks, PharmD, PhD (Director, Division of Clinical Pharmacology), the Translational Research Trials Office (TRTO), and has been funded by the Center for Clinical and Translational Science and Training (CCTST). This phase 1 trial is the first basic research effort in the Division of Critical Care Medicine at Cincinnati Children’s that has been directly translated to the bedside of critically ill children. We submitted an investigational new drug (IND) application from the FDA and are deemed safe to proceed. The trial is registered with ClinicalTrials.gov (NCT01352182).
  • Grant Support

    PPAR Gamma In Pediatric Sepsis And The Inflammatory Response In Obesity
    PI: Jennifer Kaplan
    Project Number: 5K08GM093135-02 

    PPAR Gamma And PPAR Gamma Agonists In Septic Shock
    PI: Basilia Zingarelli
    Project Number: 5R01GM067202-08