Research Interests

My research interests are directed towards understanding of the processes involved in regulating cellular growth and differentiation. In particular, I am interested in investigating the Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) receptor and its role in influencing tumor growth.

Recent studies have shown that PACAP receptors expressed on certain tumoral cells such as the rat pancreatic acinar carcinoma cell line, AR-42J, and the non-small cell lung carcinom cell line, NCIH838, are able to stimulate growth. The recent cloning of the rat and human PACAP receptor in my laboratory has shown that PACAP receptors occur as four major splice variants that are alternatively processed from a single gene and display tissue-specific expression and differential coupling to adenylate cyclase and phospholipase C. Most recently, I identified that one of these splice variants (SV-2) expressed in human tissues exhibits enhanced efficacy for coupling to phospholipase C and the induction of the immediate-early genes, c-fos, c-myc and c-jun. Parallel studies in both cell culture and in whole animals have demonstrated that PACAP stimulates the growth of non-small cell lung carcinoma cells, an effect that can be inhibited by PACAP receptor antagonists. Therefore, my current research interests are aimed at elucidating the expression and understanding the mechanisms by which PACAP receptor splice variants are able to differentially couple to signal transduction pathways and influence cellular growth and differentiation.

My short term research goals are to: 1) characterize the distribution of PACAP hormone and PACAP receptors in tumoral cells; 2) characterize their abilities to activate intracellular second messengers and immediate-early gene expression. Data developed from these studies will be critical to developing more long range research plans whereby the knowledge gained from studying the PACAP receptor can be applied to other gastrointestinal peptide receptors such as for the calcitonin gene related peptide (CGRP) receptor. The CGRP receptor is particularly interesting to study because of its importance in mediating nocioceptive pain responses and in modulating vascular resistance. These studies will fully integrate and complement parallel physiological studies already in progress by other principal investigators at CURE: VA/UCLA Digestive Diseases Research Center. My long-term goals are to characterize the PACAP receptor gene and transcriptional factors regulating the expression of PACAP-R splice variants and to develop transgenic strains of mice lacking functional PACAP receptors in order to better understand their physiologic significance.

Results obtained from these studies will constitute the basis for related publications the development of additional research expertise, and grant funding support. The study of the PACAP receptor localization and signal transduction has several implications that will potentially be beneficial to those interested in seven transmembrane, G-protein coupled receptors, and lead to a better understanding of the intracellular signaling pathways involved in regulating cellular physiology, and growth.. Results as well as techniques derived from these studies will provide the means to facilitate more productive interactions and collaborations that will benefit other members of the academic community, and ultimately, provide the basis for defining and treating human diseases that involve dysregulation of hormone-receptor mediated signaling.

In addition to these basic science projects, my clinical research interests are focused on the diagnosis and management of islet cell tumors of the pancreas such as with the Zollinger-Ellison Syndrome. Recent approaches to the pharmacologic management of the gastric acid hypersecretion for this disorder center on the use of recently developed proton pump inhibitors that block the secretion of gastric acid from the fundic parietal cells. Recently, I have been the principal investigator of two Phase I and two Phase III studies at the UCLA CRC to evaluate the proton pump inhibitor, pantoprazole. In addition, we are in the process of developing a clinical protocol for the use of the somatostatin analogue Sandostatin combined with interferon alpha for the management of metastatic islet cell tumors to the liver. In addition we are currently exploring the use of radioactive somatostatin analogues for the treatment of metastatic tumors. The availability of a CRC at our university that will permit the recruitment of patients with neuroendocrine tumors is clearly important for the development of treatment protocols for these patients.