Impaired gastric accommodation: The inability of the stomach to properly expand and hold food (gastric accommodation) plays an important role in causing the symptoms of dyspepsia. Dyspepsia affects roughly one in four Americans, leading to nausea, bloating, and abdominal pain or discomfort after a meal. The overall goals of the studies being undertaken in my lab are to provide a more thorough understanding of how the stomach relaxes to accommodate food and aid in the design of improved therapeutic strategies to restore normal stomach function and relieve the symptoms of impaired gastric accommodation.
We are doing this by carrying out a variety of experiments whose objectives are to define in more detail a novel pathway contributing to nitrergic relaxation in gastric fundus smooth muscles involving sarcoplasmic reticulum Ca2+ release and phospholamban phosphorylation by CaM kinase II. Impaired gastric accommodation is present in a high percentage of patients with functional dyspepsia, and restoration of accommodation is a desired therapeutic goal. A thorough investigation of the nitric oxide-activated signaling pathways that relax fundus smooth muscles will help to achieve this goal. To do this we are determining how phospholamban affects nitric oxide-induced relaxation and CaM kinase II activation in gastric fundus smooth muscles using phospholamban knockout mice. We are investigating the function and mechanism of CaM kinase II-sarcoplasmic reticulum association in gastric fundus smooth muscle relaxation. Finally, we are determining the role of interstitial cells of Cajal in nitric oxide-induced activation of CaM kinase II and phospholamban phosphorylation in gastric fundus smooth muscles. We employ several methodologies, including mechanical measurements of gastric fundus smooth muscles, SDS-PAGE and Western blotting of phosphorylated phospholamban, CaM kinase II assays in smooth muscle lysates and sarcoplasmic reticulum fractions, perforated-patch whole cell recordings of STOCs, sharp electrode recordings of membrane potential, and fluorescent Ca2+ indicator dyes to measure intracellular Ca2+ transients and Ca2+ waves in gastric fundus smooth muscle cells.
Ulcerative Colitis: Ulcerative colitis is a debilitating disease affecting over a half million Americans for which there is no cure. Patients with chronic ulcerative colitis or Crohn's disease exhibit reduced colonic contractility, reductions in basal colonic intraluminal pressure, and reductions in postprandial motility. In both human and animal models of colitis there is evidence that inflammatory mediators produced in the mucosa and submucosa reach the muscle layer and alter colonic muscle contractility. Current treatments for ulcerative colitis revolve around the use of anti-inflammatory drugs and immunosuppressants that cause severe side effects, and do not induce a long-term benefit in a significant percentage (40%-60%) of patients. Therefore, new therapies and approaches are needed that induce remission, alter the natural course of the disease, or relieve symptoms in ulcerative colitis patients. One approach to this end would be to understand the molecular changes occurring within the smooth muscle cells as a consequence of colonic inflammation. This approach may lead to improvements in therapies utilizing motility drugs for cases of ulcerative colitis. Regulation of intracellular Ca2+ signaling by sarcoplasmic reticulum Ca2+ cycling plays a key role in GI smooth muscle contractility. In cardiac and vascular smooth muscles, many of the signaling pathways involved in the induction of pathological remodeling are linked to SR Ca2+ cycling. Similarly, emerging evidence implicates dysregulation of intracellular Ca2+ cycling in the dysmotility of ulcerative colitis. These recent findings are providing important clues to the biochemical and molecular basis for the functional changes in colon smooth muscles that give rise to the physiological findings of colonic dysmotility of ulcerative colitis.
The overall goal of these studies being undertaken in my lab is to show that phospholamban phosphorylation by CaM kinase II regulates intracellular Ca2+ signaling in colon smooth muscle cells and that this novel pathway regulating myogenic excitability in the colon is disrupted by ulcerative colitis. To pursue this goal, we are investigating how altered phospholamban and SERCA expression, and phospholamban phosphorylation by CaM kinase II trigger the molecular remodeling that leads to the dysmotility of colon smooth muscles in ulcerative colitis. Experimental colitis is induced in wild-type C57BL/6 mice or phospholamban knockout mice with dextran sodium sulfate to analyze the intracellular and myogenic responses. We employ several techniques, including mechanical measurements of colon smooth muscles, SDS-PAGE and Western blotting, CaM kinase II assays, sharp electrode recordings of membrane potential, and fluorescent Ca2+ indicator dyes to measure intracellular Ca2+ waves in colon smooth muscle cells. These studies will lead to a better understanding of how intracellular Ca2+ handling via novel regulatory pathways is involved in colon smooth muscle excitability and how these pathways become disrupted in diseases such as ulcerative colitis. Data obtained from this proposal will aid in the design of improved therapeutic strategies to restore the normal coordinated contractile activity of the colon and relieve the symptoms associated with ulcerative colitis.
Substrate Selectivity of Calcineurin Catalytic Isoforms: An emerging question in Ca2+-dependent signaling concerns the physiological roles of the two catalytic subunits of the multifunctional Ca2+/calmodulin (CaM)-dependent Ser/Thr protein phosphatase calcineurin (CaN). The major goals of this project are to elucidate the mechanisms underlying the substrate selectivity, sub-cellular distribution, and NFAT-binding of the calcineurin a and b catalytic subunit isoforms in vascular smooth muscles.
Course Instructor, Foundations and Principles of Medical Science I/MED631 • 2012-present
Intracellular signal transduction, and molecular mechanisms of cancer for 1st year medical students.
Small Group Facilitator, Clinical Problem Solving-1• 2010-2011
Reviewed bi-weekly clinical cases and guided first year medical students through the process of diagnosing, by taking histories, and interpreting lab results, and imaging procedures 1st year medical students.
Faculty Advisor, Ob/Gyn Basic Sciences Correlations Conferences • 2007
Advised 3rd year medical students concerning basic science underlying clinical observations.
Course Coordinator and Instructor, Medical Cell Biology/PCB610 • 2002-2011
Intracellular signal transduction, and molecular mechanisms of cancer 1st year medical students.
Course Instructor, Medical Cell Biology/PCB610 • 1997-2002
Protein structure/function, intracellular signal transduction, and molecular mechanisms of cancer 1st year medical students.
Teaching Assistant, Medical Microbiology Laboratory, Boston University School of Medicine • 1985
Assist 2nd year medical students in Gram staining techniques
Graduate Student Instruction
For each Graduate School Course or Journal Club, the objectives are to teach graduate students the 7 Steps to critically evaluate a scientific paper.
Course Instructor, Neuroeffector Mechanisms/CMPP740 • 2001, 2005, 2008, 2011
Course Coordinator & Instructor, Smooth Muscle Signaling Journal Club/CMPP 794 • 2007
Course Coordinator & Instructor, Smooth Muscle Plasticity Journal Club/CMPP 794, • 2005
Course Instructor, Cell Biology/CMB710 • 2004
Course Instructor, Local and Long Distance Cellular Signaling/CMPP730 • 1999
Course Instructor, Signal Transduction Mechanisms/CMPP730 • 1996