1) Mechanisms and regulation of TNF-dependent neuroinflammation and neurotoxicity and their role in neurodegenerative disease.
A. Parkinsons’s Disease. Post-mortem examination of brains from Parkinson?s disease (PD) patients reveals the presence of activated microglial cells and elevated levels of inflammatory cytokines, including Tumor Necrosis Factor (TNF), IL1b, IL-2, IL-4 and IL-6. Our research is aimed at identifying the mechanisms and signaling pathways that regulate neuroinflammatory responses in the ventral midbrain and impact dopaminergic (DA) neuron survival. The long-term goal is to develop strategies to inhibit glial-derived neurotoxic factors, and in particular to target cytokines that drive microglial-derived oxidative stress, promote apoptosis, and contribute to degeneration of midbrain DA neurons and parkinsonism. Specifically, use of novel engineered TNF inhibitors (Steed, Tansey et al., Science 2003) as biochemical tools has enabled us to identify soluble TNF-dependent mechanisms and signaling pathways as critical players in the degeneration of dopamine neurons in several in vitro and in vivo models of PD. Results from neuroprotection studies with dominant negative TNF (DN-TNF) inhibitors in animal models of PD strongly suggest that targeting the TNF pathway may halt or slow the progressive degeneration of ventral midbrain DA neurons (McCoy et al., J Neurosci 2006) and may be useful in attenuating PD progression. Second, we have begun exploring the feasibility and efficacy of viral delivery of DN-TNFs as proof of principle for further development of anti-TNF in vivo gene therapy approaches in parkinsonian rats (McCoy et al., Molecular Therapy 2008) and plan to move forward into non-human primates in 2009. Third, we have uncovered a novel role for Regulator of G-protein Signaling-10 (RGS10) as an important regulator of the microglial stress response and as a protective factor against inflammation-induced degeneration of the nigrostriatal pathway (Lee et al., J Neurosci 2008). Lastly, in collaboration with Matthew Goldberg?s lab in Neurology, we are developing chronic, progressive and predictive mouse models of PD based on the interplay between genetics and environment. We are using inflammatory stimuli as ?second-hit? triggers in mice deficient in genes linked to forms of familial PD, to test the hypothesis that chronic inflammation can trigger disease symptoms in combination with genetic factors (Frank-Cannon, et al., J Neurosci in press). Funding for these projects comes from the Michael J. Fox Foundation of Parkinson’s Research and the NIH-NINDS
B. Alzheimer’s Disease. The pro-inflammatory status of adult brain increases as we age and recent epidemiologic and clinical studies indicate that chronic use of non-steroidal anti-inflammatory drugs can lower the risk of developing neurodegenerative disease. Genetic mutations that result in abnormal processing of Amyloid Precursor Protein (APP) result in overproduction of neurotoxic amyloid beta peptides and formation of amyloid (senile) plaques, the hallmark of Alzheimer’s Disease. Given that increasing amyloid plaque burden correlates with cognitive decline and memory loss and plaque burden is influenced by the extent to which brain-resident microglia remove and deposit fibrillar Abeta as it forms with advancing age, our research is aimed at identifying the mechanisms and signaling pathways by which TNF signaling positively or negatively regulates amyloid-beta associated neurotoxicity in normal and pathological conditions. Preliminary studies using DN-TNFs to inhibit soluble TNF signaling in a transgenic mouse model of AD demonstrate TNF affects APP processing and may contribute to the accumulation of intraneuronal amyloid in the early stages of the disease process (McAlpine et al., J Neurosci in press). Funding for this research comes from the Alzheimer’s Research grant from the American Health Assistance Foundation and from the Alzheimer’s Disease Center at UT Southwestern Medical Center.
2) Ex vivo gene therapy in models of neurodegeneration and neurotrauma. Our ultimate goal is to gain a better understanding of the mechanisms that contribute to neurodegeneration in order to develop new preventative or therapeutic interventions for the treatment of neurodegenerative diseases. Therefore, an additional area of investigation for our lab entails investigation of the cellular/molecular properties and neurorestorative potential of a stromal cell population from adult adipose which we term Adipose-Derived Adult Stromal (ADAS) cells. Previous efforts in our lab demonstrated that these cells have very limited capacity to differentiate into mature and functional neurons in culture (Wrage, Thran et al., PLoS ONE 2008); yet autologous ADAS transplants promote functional recovery in models of parkinsonism (McCoy, Martinez et al., Experimental Neurology 2008) and spinal cord injury (Martinez, Wrage et al., J Neurosci in preparation). Future efforts may be geared toward exploring the extent to which ADAS cells can be used in ex vivo gene therapy to deliver trophic and/or anti-inflammatory factors to aid in CNS repair. Funding for this research comes from the National Parkinson Foundation and the National Institutes of Health-NINDS.
RESEARCH INTERESTS
Neuroinflammation/neurodegeneration
Neuronal survival/differentiation
Neurorestoration/cell replacement
Animal models of neurodegeneration
Anti-TNF gene therapy
RECENT PUBLICATIONS
Lee, J.K., McCoy, M.K., Harms, A.S., Ruhn, K.A., Gold, S.J., Tansey, M.G., "Regulator of G-protein signaling-10 (RGS10) promotes dopaminergic neuron survival via regulation of the microglial inflammatory response" J Neuroscience, 28:8517-28, 2008
McCoy, M.K., Ruhn, K.A., Martinez, T.N., McAlpine, F.E., Blesch, A., Tansey, M.G., "Intranigral lentiviral delivery of dominant negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats" Mol Therapy, 16(9):1572-9, 2008
McCoy*, M.K., Martinez*, T.N., Ruhn, K.A., Wrage, P.C., Keefer, E.W., Botterman, B.R., Tansey, K.E., Tansey, M.G., (2008), "Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson" Experimental Neurology, 210:14-29, 2008
Wrage, P.C., Tran, T., To, K., Keefer, E.W., Ruhn, K.A., Hong, J., Hattangadi, S., Trevi?o, I., and Tansey M.G, "The neuro-glial properties of adipose-derived adult stromal (ADAS) cells are not regulated by Notch 1 and are not derived from neural crest lineage" PLoS ONE, 3:1453, 2008
SIGNIFICANT PUBLICATIONS
Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O’Brien C, O’Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI, "Inactivation of TNF signaling by rationally designed dominant-negative TNF variants." Science, 301(5641):1895-8, September 2003
McCoy MK, Martinez TN, Ruhn KA, Szymkowski DE, Smith CG, Botterman BR, Tansey KE, Tansey MG, "Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson’s disease." J Neurosci, 26(37):9365-75, September 2006
Yang X, Tomita T, Wines-Samuelson M, Beglopoulos V, Tansey MG, Kopan R, Shen J, "Notch1 signaling influences v2 interneuron and motor neuron development in the spinal cord." Dev Neurosci, 28(1-2):102-17, 2006
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