CELL BIOLOGY GRADUATE PROGRAM

Karin Westlund High, Ph.D.

Credentials

B.A., University of Texas (Austin), 1975, M.A., 1976
Ph.D., University of Texas Medical Branch (Galveston), 1981
Member, Marine Biomedical Institute
Professor, Anatomy & Neurosciences
Cell Biology Graduate Program
Neurosciences Graduate Program

Our research at The University of Texas Medical Branch has primarily been directed toward the study of  pain transmission mechanisms interacting with immune mechanisms in the via neurotransmitter receptors. Study of the interactions of these systems is designed to determine the synaptic mechanisms underlying pain and improving analgesia for patients with debilitating pain.

Two recearch projects are underway in the lab to determine effective means of eliminating (1) neuroinflammatory arthritic pain and (2) debilitating pancreatic pain common in pancreatitis and pancreatic cancer. 

Collaborators:

Karin Westlund, Ph.D.                 Dept. of Anatomy and Neurosciences,          

Terry McNearney, M.D.              Dept. of Anatomy and Neurosciences,   

                                                   Division of Rheumatology, UTMB

NIH PO1 Project 2   “Neurogenic Contributions to the Initiation and Persistence of Arthritis” (08/01/01-07/31/06), $185,702

 R21 AR48371 “Glutamate Induced Molecular Events Contributing to Chronic Arthritis” (09/28/01-06/31/03), 30%,  $74,500

 Dana Foundation “Neurogenic Contributions to the Initiation and Persistence of Arthritis” (07/01/02-06/30/05), $300,000

           Two research projects are underway in the lab to determine effective means of eliminating (1) neuroinflammatory arthritic pain and (2) debilitating pancreatic pain common in pancreatitis and pancreatic cancer.

        Over 90% of the population will suffer at least one form of arthritis over their lifetime. Present treatment regimens cannot completely stop the inflammation of arthritis, which often results in significant pain and disability. The US spends an estimated 60 billion/ year in total costs of medicines, disability and lost wages (Arthritis Foundation 2002).

A hypothesis was forged through collaboration between neuroscience, molecular, and immunology labs that is allowing a focused study of neurotransmitter glutamate activation of immunological responses in the joints. A novel route to inflammation is being pursued, and it is hoped that its interruption results in a more effective and longer remission for arthritis patients. We have clinical and laboratory evidence that we can diminish the inflammation and pain of arthritis in humans by blockade of glutamate receptor mediated events in joint tissues. We hope that through consideration of neuroimmunomodulation events a new treatment will be developed that alone or in tandem with existing therapies will preserve quality of life and improve pain levels and joint function for arthritis sufferers. This can be accomplished through support of these research efforts, enhanced clinical care staff, and greater educational opportunities for trainees and patients about early prevention and effective treatment of arthritis.

            It is known that substances derived from the nervous system can contribute to the inflammation, including the joint inflammation of arthritis. This is reflected in spurious case reports showing that some patients with stroke or nerve damage will not experience arthritis changes, or in some cases have a lessening of arthritis, on the paralyzed side of the body. Glutamate and related amino acids are small proteins that activate glutamate receptors on cell surfaces. The levels of glutamate in the nervous tissues are very tightly controlled, because glutamate receptor activation causes a large reaction in the nerve cells including inflammation and even cell death. Most of the studies of glutamate receptor activation have been performed on nerve cells, but our lab and others have demonstrated these receptors on non-nervous tissue in the periphery, including joint tissue. Study is focused on glutamate-mediated activation in the joints using animal models, human clonal and primary synoviocyte cultures and clinical samples to determine the role of the neurotransmitter glutamate in the development of arthritis. Treatment strategies are then designed to stop neurotransmission in this neuronal pathway in states of inflammatory activation. This study will significantly contribute to the field of neuroimmunology with knowledge that can be extended to other peripheral systems.

            We study the signal transduction processes initiating subcellular activation, electrical changes in the nerves involved with the joint and behavioral changes in the rat, which reflect increased sensitivity of the arthritic limb. We know from our previous acute arthritis studies in animals that glutamate receptor blockade decreases the arthritis pain. Compounds called protein kinase inhibitors block the normal machinery of the cell that upregulate proteins involved in inflammation. Preliminary studies in animal models have shown that one inhibitor decreases arthritic pain. We will use these types of compounds to see if they can stop the inflammatory cascades and pain associated with glutamate receptor activation. These inhibitors will first be safety-tested in human and rat synoviocyte cultures and ultimately tested for efficacy and safety in animal models.

            The studies described above are designed to identify and characterize a novel pathway of inflammation where its interruption would result in a more effective and longer remission for arthritis patients. The studies are providing important information about the interface between the nervous system and peripheral site of inflammation. We will have clinical and laboratory evidence that we can diminish the inflammation and pain of arthritis in humans by blockade of glutamate receptor mediated events in joint tissues. We hope that this new treatment alone or in tandem with existing therapies will preserve quality of life and improve pain levels and joint function for arthritis sufferers.

  Recent References:

 Zhang, L., Hoff, A.O., Wimalawansa, S.J., Cote, G.J.,  Gagel, R.F., and Westlund, K.N.       Arthritic calcitonin/a calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity, PAIN 89: 265-273, 2001.

 Zhang, L., Lu Y., Chen Y., Westlund, K. Group 1 Metabotropic Glutamate Receptor Antagonists Block Secondary Thermal Hyperalgesia in Rats with Knee Joint Inflammation, J. Pharmacology and Experimental Therapeutics, 300 (1) 149-156, 2002.

 Hendiani, J.A., Westlund, K.N., Lawand N., Goel, N. Lisse, J., and McNearney, T. Mechanical Sensation and Pain Thresholds in Patients with Chronic Arthropathies. J. Pain 4(4):203-211, 2003.

PROJECT 2       PANCREATITIS

RO1 NS39041 (Westlund High, Karin N.)       funded         04/01/2000 - 03/31/2004

                                                                                                $200,000

                                                                        renewed         04/01/2004 – 03/31/2008

                                                                                                $250,000

 Many patients with pancreatitis or pancreatic cancer complain of abdominal pain that is resistant even to morphine. Our previous studies have determined that pain in patients with cancer involving the pelvic visceral organs is relieved by a neurosurgical lesion limited to the midline of the dorsal column of the spinal cord. We determined that sensory input from the pancreas is primarily transmitted to higher brain sensory processing centers as a midline component of the postsynaptic dorsal column pathway using anatomical, electrophysiological, behavioral and fMRI methods. In our laboratory we have recently developed a model of persistent visceral pain (two weeks) in Lewis inbred rats that resembles an acute attack of human pancreatitis in blood values and histology. The rats exhibit behavioral changes that parallel those of cancer patients such as malaise and decreased physical activity.  We will soon be developing a model of pancreatic cancer in rats for similar studies.             These studies are designed to understand how sensitization of this newly described pathway can lead to persistent visceral pain states and how they can be alleviated.