Summary
Publications
Cellular Regulation of Upper Gastrointestinal (GI) Motility
The primary focus of my research is to better understand how excitatory and inhibitory neurotransmitters and agonists control the Ca2+ sensitization mechanisms of the contractile apparatus that manage myosin light chain phosphorylation and adjust the smooth muscle contractions that underlie gastric motility. We are interested in how stomach emptying is regulated by the secreted protein Mfge8. Mfge8 binding to α8integrin on smooth muscles of the gastric antrum reduces stomach contractions by inhibiting Rho kinase phosphorylation of MYPT, resulting in myosin phosphatase activation, myosin light chain dephosphorylation, and reduced contractile force. Thus, Mfge8 acts as a brake on stomach contractions to reduce the rate of gastric emptying. It is unknown whether Mfge8 expression and α8integrin binding is a constitutive, or responsive regulatory mechanism that changes during digestion and fasting. A major focus of our research is to investigate how feeding and fasting affects Mfge8 secretion, α8integrin binding, and gastric emptying.
Precise regulation of gastric emptying is critical for optimal nutrient absorption in the small intestine. The two most common gastric emptying disorders are delayed gastric emptying, or gastroparesis, and rapid gastric emptying, or dumping syndrome. Each condition is associated with significant health care burdens and morbidity, with debilitating symptoms and poor quality of life, and an increased risk for harmful complications including erratic glycemic control, malnutrition, weight loss or inability to gain weight, vitamin, mineral, and calorie malabsorption, and altered absorption and efficacy profiles of oral medications. The overall goal of our research is to expand our knowledge of the cellular and molecular mechanisms regulating gastric emptying to establish broader and better arrays of approved treatment options.
In collaboration with Dr Caroline Cobine, we are also examining the regulation of Ca2+sensitization mechanisms in the lower esophageal sphincter (LES). The overall goals of these studies are to understand the key signaling pathways controlling LES contractility to identify potential targets for novel therapeutic strategies for improving LES function in upper GI disorders such as GERD and achalasia. My laboratory utilizes a variety of complementary experimental approaches that encompasses molecular biology, biochemistry, cell biology, and physiology, with specific training and expertise in these key research areas:
Jess - Wes automated capillary electrophoresis and immunodetection for protein expression and phosphorylation analysis.
Confocal Immunofluorescence Microscopy - Standard immunofluorescence and immunofluorescent proximity ligation assay (PLA) are used to provide spatial protein expression, interactions, and phosphorylation data in cryostat and whole mount tissue sections. This provides molecular detection in a morphological context to localize proteins within specific cell populations in an intact tissue to better understand how specific cellular protein expression affects intracellular and intercellular cell-cell signaling.
Spatial Transcriptomics utilizing RNAscope - RNAscope is a novel multiplex nucleic acid in situ hybridization technology that provides spatial transcriptomic expression data for the sensitive detection, characterization, and detailed localization mRNA at single-cell resolution, capturing gene expression patterns that can be visualized in situ. This provides molecular detection in a morphological context to localize gene expression within specific cell populations within an intact tissue to better understand how specific cellular gene expression affects cell-cell interactions.
Muscle Function Measurements - The use of isolated tissues in the study of physiological and pharmacological function of organs has been performed for nearly a century. Central to the isolated tissue bath assay is the ability to measure concentration-dependent changes to isometric contraction, and how the efficacy and potency of contractile agonists can be manipulated by knock-out or knock-in of specific proteins, as well as by the use of specific antagonists or inhibitors.However, the underlying electrical, biochemical (second messengers) and ionic (ion fluxes) alterations that mediate these responses are obviously important aspects of muscle function. To a large extent, these properties can only be analyzed from specific muscle tissues studied in isolation using physiological buffers and temperatures.
Education
- Postdoctoral, Vollum Institute, Oregon Health Sciences University, 1995
- Postdoctoral, Vanderbilt University School of Medicine, 1991
- Ph.D., Boston University, 1989
- B.S., Syracuse University, 1981