Dennis D. Cunningham

Picture of Dennis D. Cunningham
Professor, Microbiology & Molecular Genetics
School of Medicine
Senior Associate Dean, Academic Affairs, College of Medicine
PH.D.
Phone: (949) 824-7074, 5267
Fax: (949) 824-8598
Email: ddcunnin@uci.edu
University of California, Irvine
B240B, B268 Med Sci I
Mail Code: 4025
Irvine, CA 92697
Research Interests
Proteases and protease nexins: regulation of neural cells
Academic Distinctions
Appointments
Research Abstract
Over the past fifteen years, Dr. Cunningham and his colleagues have identified and studied two protease inhibitors called protease nexins (PNs) that regulate certain proteases in the extracellular environment. The PNs are synthesized and secreted by a variety of extravascular cells including fibroblasts, smooth muscle cells, neurons and astrocytes. They bind and inhibit certain serine proteases by forming a complex with their catalytic site serine residue. The complexes bind back to the cells and are rapidly internalized and degraded. This provides a mechanism for regulating and clearing serine proteases in the extracellular environment. This localized regulatory mechanism is well suited for the brain because the blood brain barrier prevents plasma protease inhibitors from entering the brain.


PN-1 is a 43 kDa protein that rapidly inhibits thrombin, urokinase and plasmin. PN-1 binds to the extracellular matrix; this accelerates its inhibition of thrombin and blocks its inhhibition of urokinase and plasmin. Thus, PN-1 is a specific thrombin inhibitor. PN-1 and thrombin regulate a number of key activities of cultured neurons and astrocytes: neurite outgrowth, astrocyte stellation and cell proliferation. PN-1 and thrombin also regulate neuron and astrocyte viability after injury/trauma. PN-1 is identical to the glial-derived neurite promoting factor or glial-derived nexin. The activity of PN-1 is markedly reduced in Alzheimer's disease (AD) postmortem brain compared to age-matched control brain with similar postmortem times. Current results suggest that this is due to increased thrombin in the AD brain and formation of PN-1-thrombin complexes. mbalances in PN-1 and thrombin in AD could lead to altered neurons and astrocytes and contribute to the pathology of the disease. In normal human brain, much of the PN-1 occurs around blood vessels, suggesting a protective role against extravasated thrombin under conditions in which the blood brain barrier is compromised.


PN-2 is a 110 kDa protein that inhibits blood clotting factors IXa, XIa, trypsin, chymotrypsin, and the epidermal growth factor binding protein. PN-2 is contained in alpha-granules of platelets and is released upon platelet activation. This finding, along with its potent inactivation of factors IXa and XIa, suggests that PN-2 may participate in the regulation of blood clotting at wound sites. PN-2 is also present in brain and is identical to the secreted form of the amyloid b-protein precursor. The b-protein is the major component of neuritic plaques and cerebrovascular deposits that characterize AD. Under normal conditions, the precursor is processed in the middle of the b-protein domain to yield PN-2. In AD, this processing is altered such that the b-protein, but not PN-2, is liberated from the precursor. A focus of research in many labs is to delineate the mechanisms that underlie these processing events and to understand the normal biological functions of PN-2.
Publications
Creatine Kinase, an ATP-generating Enzyme, is Required for Thrombin Receptor Signaling to the Cytoskeleton. Vinit B. Majahan, Karnire S. Pai, Alice Lau and Dennis D. Cunningham. Proceedings of the National Academy of Sciences, USA, 97, 12060-12067, 2000.
Injury-related Factors and Conditions Down-regulate the Thrombin Receptor (PAR-1) in a Human Neuronal Cell Line. Jonathon R. Weinstin, Alice Lau, Lawrence Brass and Dennis D. Cunningham. Journal of Neurochemistry, 71, 1034-1050 (1998).
Signaling Pathways Involved in Thrombin-induced Cell Protection. Frances M. Donovan and Dennis D. Cuningham. Journal of Biological Chemistry, 273, 12746-12752 (1998).
Thrombin cause a Marked Delay in Skeletal Myogenesis which Correlates with the Delayed Expression of Myogenin and p21CIp1/WAF1. Denis C. Guttridge, Alice Lau, Lynn Tran and Dennis D. Cunningham. Journal of Biological Chemistry, 272, 24117-24120 (1997).
Thrombin Induces Apoptosis in Cultured Neurons and Astrocytes Via a Pathway Requiring Tyrosine Kinase and RhoA Activities. Frances M. Donovan, Christian J. Pike, Carl W. Cotman and Dennis D. Cunningham. Journal of Neuroscience, 17, 5316-5326 (1997).
Graduate Programs
Neurobiology
Last updated
03/05/2002