title: PKD signaling and pancreatitis.
abstract: BACKGROUND
  Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases.
  
  
  METHODS
  This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models.
  
  
  RESULTS
  Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis.
  
  
  CONCLUSIONS
  These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder.
authors.affiliation: West Los Angeles VA Healthcare Center, UCLA/VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Bldg 258, Rm 340, Los Angeles, CA, 90073, USA. jzyuan@ucla.edu.
authors.forename: Jingzhen
authors.initials: J
authors.lastname: Yuan
authors.affiliation: West Los Angeles VA Healthcare Center, UCLA/VA Greater Los Angeles Healthcare System, 11301 Wilshire Blvd, Bldg 258, Rm 340, Los Angeles, CA, 90073, USA.|Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pandol
mesh_terms: D061354:Acinar Cells; D006801:Humans; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017346:Protein Serine-Threonine Kinases
keywords: Acinar cell necrosis; NF-κB activation; Pancreatitis; Protein kinase D; Zymogen activation