The Courses I Teach:

Bio 321, 322 Anatomy and Physiology I and II

Bio 495/595 Neurobiology

Bio 333 Contemporary Issues in Life Sciences

My Background

Detailed information can be found in my Curriculum Vitae or in my recent publications (insert key words here). I have spent 10 years doing basic medical research at the Mayo Clinic in Rochester, MN. Three more years were spent in Drug Discovery for Bristol Myers Squibb. Both jobs were extremely rewarding and made use of my skills as a biophysicist, as a physiologist, and my ability to communicate effectively (i.e. writing ability and verbal communication are important!). Even more detailed information about my professional life can be found in my curriculum vitae.

Expertise:

Gastrointestinal physiology (motility)

Cardiovascular physiology

Regulation of ion channel function.

Current Research: I am mainly interested in the molecules that enable cells to communicate with the environment (ion channels and G-protein coupled receptors), and how these cellular components enable a cell to contribute to the function of an organ, and ultimately the entire organism. This is called Integrative Physiology. My laboratory uses several techniques including muscle tension recording, electrophysiology, fluorescence microscopy, molecular and cellular biology, and mathematical modeling. The primary interests include gastrointestinal motility, cardiac electrophysiology, and endocrine function as it relates to insulin secretion and obesity. Experiments may be performed in-silico (mathematical modeling), in cell culture systems (expresses ion channels or GPCR’s), or using freshly dissected tissues. I hope to develop novel models for gastrointestinal motility in the Burmese python snake and the zebrafish.

Potential Projects: I am in the process of writing grants to fund work in my laboratory. The following describes 2 potential projects, and here is the brief summary. One involves a cell culture assay to explore the mechanisms that control sensitivity of the enteric nervous system, i.e. the sensitivity to the nerves in the gastrointestinal tract, to motilin. Under normal conditions motilin will stimulate excititatory activity of neurons leading to contraction of gastrointestinal smooth muscles. The second project uses molecular biological techniques to determine if the motilin receptor is present in the gastrointestinal tissues of the Zebrafish and the Python snake. This information is necessary to determine if these animal species may be a useful model system to develop to explore the regulation of the motilin receptor.

Project 1: How is sensitivity to motilin regulated?

Stimulation of G-Protein-coupled receptors (GPCR’s) initiates cell signaling and signal desensitization. In some cases receptor activation always leads to desensitization. This can be a problem for drug treatment. For example, stimulating the motilin receptor will enhance GI motility, the desired effect. The drawback is that activation of the receptor leads to strong desensitization. Therefore drug treatment becomes ineffective over time because the receptor has desensitized! One important question is whether unique ligands (i.e. drugs) can be found that activate but do not desensitize. This project will begin to examine this question using the motilin receptor, GPR 38. The motilin receptor is expressed on smooth muscle and enteric neurons in the gastrointestinal tract. Stimulation of the motilin receptor results in the coordinated contraction of smooth muscles in the gastrointestinal tract, and thereby enhances gastric emptying. Failure of the stomach to accommodate ingested food and impaired gastric emptying are unpleasant. Diabetics have a high prevalence of symptoms (>40% suffer from delayed gastric emptying). These "functional bowel disorders" are the focus of intense academic and pharmaceutical research with the objective of identifying new, effective treatments. Development of a motilin receptor agonist to treat delayed gastric emptying has been pursued by the pharmaceutical industry.

Project 2: Does a motilin receptor (motilin-R) orthologue exist in the Burmese python snake (Python molurus) and the zebrafish, (Danio rerio)?

The motilin-R is a G-Protein-coupled receptor (GPCR) that regulates gastrointestinal motility in humans. It is expressed on smooth muscle and enteric neurons in the gastrointestinal tract. Activation of the motilin-R results in stimulation of gastrointestinal motility. Motilin-R orthologues, i.e. genes with similar structure and function to the human motilin-R, have been identified in several species including the rabbit and the dog, but not in rodents. This is problematic because most gastrointestinal studies performed in living organisms (in-vivo) utilize rodent models. Therefore a new model system is needed to examine the motilin-R in-vivo. The first step in development of any model system will be to determine if a motilin-R orthologue exists. The primary objective of this project is to determine if the python and the zebrafish express a putative motilin-R orthologue, i.e. a gene with similar structure as the human motilin-R. There is a good chance that an orthologue exists in the python because the natural ligand for the motilin-R, a small peptide called motilin, is found in blood samples from the Python snake. After feeding, the python snake has large increases in the plasma concentration of regulatory peptides that determine gastrointestinal function (S. Secor et al, PNAS 98:136371-13642, also see a description of Secor’s work). These regulatory peptides control a dramatic proliferation of the mucosal layer of the gastrointestinal tract that is needed for nutrient absorption. The chances for finding an orthologue in the zebrafish is also high because of the close similarity between the zebrafish and the human genome. The zebrafish is rapidly becoming the favorite model system for developmental biology.

Background:

G-Protein-coupled receptors (GPCR’s) are proteins that allow cells to communicate with the surrounding environment. Many cellular events such as muscle contraction, hormone secretion, and neural signaling for pain or motivation are affected by GPCR’s. Hence specific GPCR’s control or modulate specific physiological functions. This project will examine the regulation of one type of GPCR, the motilin receptor. The motilin receptor is expressed on smooth muscle and enteric neurons in the gastrointestinal tract. Stimulation of the motilin receptor results in the coordinated contraction of smooth muscles in the gastrointestinal tract, and thereby enhances gastric emptying. Therefore it may be possible to develop a drug that will stimulate the motilin receptor, (i.e. a motilin receptor agonist) and enhance gastric emptying. Why is it important to develop such a drug? When the stomach fails to accommodate ingested food and/or gastric emptying is impaired the feelings can be very unpleasant. Diabetics have a high prevalence of these symptoms (>40% suffer from delayed gastric emptying). There are few effective treatments for this type of gastrointestinal disorder. These "functional bowel disorders" are the focus of intense academic and pharmaceutical research with the objective of identifying new, effective treatments.

Ion Channels are proteins in the plasma membrane that allow ions, such as K⁺, Na⁺, or Cl^-, to cross the plasma membrane to get in, or get out of cells. They are important in many, many cellular events including generate of a nerve action potential, contraction of muscle cells (smooth muscle, skeletal muscle, or cardiac muscle), neurotransmitter release, and the secretion of hormones like insulin. Since these proteins regulate cellular function, and ultimately the function of tissues, they are good drug targets to control physiological processes.

Cool Research Images:

Confocal Microscopy Data: A confocal microscope allows serial sectioning, and has high spatial resolution. High spatial resolution means that the confocal microscope has the ability to distinguish between 2 points that are very close together…. If two proteins are close together the confocal microscope can show you that instead of seeing a smear of two separate structures. Here are some examples:

1. Expression of the motilin receptor in HEK 293 cells. This is a cell stack, or a series of images that start at the bottom of the cell and end at the top. Notice that the receptor is primarily located in the plasma membrane, at the edge of the cell. (cell1stack.avi)

2. Using software the series of images that ‘slice’ through the object may be put back together, or reconstructed. This image can rotated so that it can be viewed form any angle. This is shown in this stack reconstruction.

3. The confocal microscope can also be used to measure intracellular calcium concentration. In some cases changes in cell calcium are localized to small regions within the cell. These changes are vital to cell function, which may include contraction of a muscle cell or release of hormones form an endocrine cell. Oscillations in cell calcium control release of insulin after eating a meal. One example of oscillations in cell calcium in a pancreatic beta cell isolated from a rat is shown here.