Research Interests of the Tansey Lab:
1) Mechanisms of TNF-dependent neuroinflammation and neurotoxicity and their role in etiology and progression of neurodegenerative disease.
A. Parkinsons's Disease. Since post-mortem examination of SN from PD patients reveals a massive astrogliosis, 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 neurotoxic mechanisms and signaling pathways associated with neuroinflammation and developing strategies to inhibit the glial reaction and/or targeting inflammatory cytokines which promote apoptosis and act to sustain the cycle of microglial-derived oxidative stress that elicits degeneration of ventral DA neurons and parkinsonism. Specifically, use of novel engineered TNF inhibitors as biochemical tools has enabled us to identify soluble TNF-dependent mechanisms and signaling pathways required for degeneration of dopamine neurons in several in vitro and in vivo models of PD. In addition, use of these dominant negative TNF inhibitors in neuroprotection studies in animal models of PD strongly suggests that targeting the TNF pathway may halt or slow the progressive degeneration of ventral midbrain DA neurons. Therefore, we are exploring the feasibility and efficacy of lentiviral delivery of DN-TNFs as proof of principle for further development of anti-TNF in vivo gene therapy approaches. Funding for these projects comes from the Michael J. Fox Foundation of Parkinson's Research.
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 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 microglial activities and amyloid-beta associated neurotoxicity in normal and pathological conditions. 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) Characterization of alternative cell sources for cell replacement strategies in neurodegenerative conditions.
A new area of investigation for our lab entails unveiling the cellular, molecular properties and neurorestorative potential of a stromal cell population from adult adipose which we term Adipose-Derived Adult Progenitor (ADAP) cells. Our efforts are aimed at investigating the developmental origins, the role of Notch signaling in neuro-glial fate induction and maturation of this progenitor population, their self-renewal/proliferation capacity, and the phenotypic stability of neurally differentiated ADAPs in vitro and in vivo after transplantation. Efforts are also aimed at assessing the therapeutic potential of ADAPs in lesion models (PD and SCI) and mechanisms by which they contribute to functional restoration of circuitry and normalize locomotor behavior. Funding for this research comes from the National Parkinson Foundation and the National Institutes of Health-NINDS.
Research in the Tansey lab is supported by the Michael J. Fox Foundation for Parkinson's Research, the National Parkinson Foundation, the Alzheimer Disease Center at UTSW, the American Health Assistance Foundation and the National Institutes of Health.
Top of page
