Image of Cunningham, Timothy

Timothy Cunningham, PhD

Professor

  • Department:Neurobiology and Anatomy
  • Education: PhD - University of Washington School of Medicine (1972); AB in Chemistry - Whitman College (1968); Postdoctoral Fellowship - Vanderbilt University (1972-1974)
Research Overview

Research interests: Neuron survival and death, neuroinflammation, central nervous system repair.

Lab Members

Research Assistant:
Lihua Yao

Graduate Students:
Shuyan Chen
Angel Lucena
Adam J. Junior

Research

Our research program has evolved out of a basic interest in the biology of cell survival and death. In most regions of the CNS, neurons that die because of trauma or nutritional losses are not replaced, which limits the healing that is required for recovery of lost behavioral function. But like all cells, neurons have natural defense mechanisms that allow them to survive when exposed to potentially life-threatening situations, for example, after a head injury, interruption of the blood supply, autoimmune disease, or the attack of inflammatory cells that accompanies all these conditions. The nerve cells that escape death in such situations are usually proficient at reorganizing their processes and the circuits they form with other nerve cells. In fact, it is this ability of surviving neurons to reorganize that is the basis for much of the long-term recovery observed following damage to the brain or spinal cord.

We have attempted to identify some of the factors that regulate the protective responses of neurons following lesions to the nervous system. The idea is to augment the cell's natural defenses so that more survive after the lesions. It is hoped that new drugs can be developed from these studies, and used to treat both acute CNS injuries and the deterioration of nervous tissue that occurs in the course of progressive neurodegenerative disorders (like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis).

Increasing neuron survival with new anti-inflammatory proteins and peptides

Interestingly, molecules that inhibit the immune systems natural response to tissue damage are often neuroprotective, so we are very interested in the activity of inflammatory cells responding to the neurons as the latter degenerate. Part of the mechanism stressed cells use to stay alive may include production of factors that thwart the inflammatory cells. As part of these studies, we stressed a human neural cell line in tissue culture with hydrogen peroxide, assuming such self-protective agents would be produced by the cells [Since this cell line was essentially cancerous, it was presumed to have many such protective mechanisms]. We isolated and identified the amino acid sequence of a novel human polypeptide called DSEP (for diffusible survival evasion peptide) from the culture medium of the cells. When the DNA coding for this molecule was transfected into mouse neural cells (causing them to produce excessive quantities of DSEP), they became very hard to kill in tissue culture. They also survived when transplanted in the brain, whereas nontransfected cells died. As expected, these transfected cells appeared to inhibit the activities of monocytes and macrophages, and microglia in the nervous system. These are all immune cells that originate in the blood and participate in the inflammatory and immune responses accompanying trauma and nervous system disease. The activity of inflammatory cells is in fact a major cause of the neuron death that is found in nervous system disorders.

We also discovered a small peptide fragment of this new polypeptide could be used like a drug, in that it protected nerve cells after it was injected into animal models of neurodegenerative disorders. This small peptide, which we call CHEC-9, was determined to be a broad spectrum uncompetitive inhibitor of secreted phospholipases A2 (sPLA2) - enzymes traditionally thought to be part of the acute or early response to inflammation.The fact that CHEC-9 was an uncompetitive inhibitor made it ideal for application to inflammation and for use in vivo. We are now using this inhibitor, along with a bioactive modifications to study the contribution of sPLA2 enzymes to the neuron death that occurs after trauma or during nervous system diseases.

CHEC peptides and sPLA2 enzymes: Applications to human disease

Reports of our recent studies with CHEC-9 can be found here and here. This and other ongoing research in the lab, as well as the work of others, now suggests that secreted phospholipase A2 (sPLA2) enzymes are directly involved in the pathology of several neurological diseases. Currently our work includes examining sPLA2 activity in human patients with Multiple Sclerosis and Amyotrophic Lateral Sclerosis, and treatment of animal models of MS, ALS, spinal cord injury, traumatic brain injury and systemic inflammation, with peptide inhibitors of sPLA2. Recent experiments also suggest CHEC-9 might be effective for reducing sPLA2 activity for humans with these diseases.

Two of the bioactive CHEC peptides models by VEGA zz 

Publications

Selected Publications

"Secreted Phospholipase A2 Involvement in Neurodegeneration: Differential Testing of Prosurvival and Anti-Inflammatory Effects of Enzyme Inhibition"
Chen, S Yao, L, and Cunningham, TJ
PLoS ONE 7(6): e39257, 2012.

"Uncompetitive Phospholipase A2 Inhibition by CHEC Sequences including Oral Treatment of Experimental Autoimmune Myeloencephalitis"
Cunningham TJ, Yao L, Greenstein JI.
Open Enzyme Inhibition. Submitted 2009.

"Product inhibition of secreted phospholipase A2 may explain lysophosphatidylcholine's unexpected therapeutic properties"
Cunningham TJ, Yao L, Lucena A
Journal of Inflammation. 5:17, 2008.

"Inhibition of secreted phospholipase A2 by neuron survival and anti-inflammatory peptide CHEC-9"
Cunningham TJ, Maciejewski J and Yao L.
J. Neuroinflammation. 3:25, 2006.

"Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis"
Cunningham TJ, Yao L, Oetinger M, Cort L, Blankenhorn EP, Greenstein JI.
J. Neuroinflammation. 3:26, 2006.

"Systemic Treatment of Cerebral Cortex Lesions In Rats With A New Secreted Phospholipase A2 Inhibitor"
Cunningham TJ, Souayah N, Jameson MB, Yao L
J. Neurotrauma, 21:1683-1691, 2004.

"Identification of the human cDNA for new survival/evasion peptide (DSEP) Studies in vitro and in vivo of overexpression by neural cells"
Cunningham TJ, Jing H, Akerblom I, Morgan R, Fisher TS, Neveu M
Exp. Neurol. 177:32-39, 2002.

"Calreticulin binding and other biological activities of survival peptide Y-P30 including effects of systemic treatment of rats"
Cunningham TJ, Jing H, Wang Y, Hodge L
Exp. Neurol. 163:457-468, 2000.

"Identification of a survival-promoting peptide in medium conditioned by oxidatively stressed cell lines of nervous system origin"
Cunningham TJ, Hodge l, Speicher D, Reim D, Tyler-Polz C, Levitt P, Eagleson, K, Kennedy S, Wang Y
J. Neurosci. 18, 7047-7060, 1998.

"Induction of opiod receptor-mediated macrophage chemotactic activity following neonatal brain injury"
Milligan CE, Webster L., Piros ET , Evans CJ, Cunningham TJ, Levitt P
J. Immunol. 154:6571-81, 1995.

"Recovery of Frontal Cortex mediated visual behaviors following neurotrophic rescue of axotomized neurons in medial frontal cortex"
Haun F, Cunningham TJ
J. Neurosci. 113:614-622, 1992.

"Brain macrophages and microglia respond differently to lesions of the developing and adult visual system"
Milligan CE, Levitt P, Cunningham TJ
J. Comp. Neurol. 314:136-146, 1991.

"Rescue of both rapidly and slowly degenerating neurons in the dorsal lateral geniculate nucleus of adult rats by a cortically derived neuron survival factor"
Eagleson, KL, Cunningham TJ, Haun F
Exp. Neurol. 116:156-162, 1992

Cunningham TJ. Naturally occurring neuron death and its regulation by developing neural pathways. In: International Review of Cytology, Vol 74. G.F. Bourne and J.F. Daniell (eds.) Academic Press, New York:163-186, 1982.

Teaching

Dr. Cunningham is a professor in the Department of Neurobiology & Anatomy at Drexel University College of Medicine. He has been with Drexel and its predecessor institutions since 1975.

He served as a regular member of the Neurology B2 Advisory Panel for the National Institutes of Health from 1989 to 1994, and is the chief scientific officer of Pultis Biotechnology.

Research Location

Department of Neurobiology and Anatomy
2900 Queen Lane
Philadelphia, PA 19129
Phone: 215-991-8505
Fax: 215-843-9082

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