Medical Student Research Fellowship for Summer 2006
Mentor: Malu G. Tansey, Ph.D
Room number: ND13.300CA
Mail Code: 9040
Phone number: 214 645-6037
Project title: mouse models of inherited Parkinson's disease
Human subjects IRB approved project number (where applicable): N/A
Animal subjects IRB approved project number (where applicable): APN# 0949-05-10-1 and 0949-06-04-1
Project Type: Animal-based and basic research projects are available
Brief Description of Project:
The Tansey lab is focused on identifying how neuroinflammatory mechanisms contribute to neurodegeneration in in vitro and in vivo models of Parkinson's (PD) and Alzheimer's (AD) disease with the long-term goal of developing new anti-inflammatory strategies to prevent or slow down the course of these diseases in humans.
Based on the knowledge that sporadic PD is multifactorial and genetic as well as environmental factors contribute to an individual's risk for developing the disease, we are testing the hypothesis that chronic systemic inflammatory stimuli represent required 'second-hits' for development of PD. In this model, the major immune surveillance cells in the brain (microglia) create a self-sustaining cycle of inflammation, pro-inflammatory cytokine and chemokine secretion that enhances oxidative stress for midbrain dopaminergic (DA) neurons and contributes to their degeneration.
Our studies using novel engineered dominant negative Tumor Necrosis Factor (DN-TNF) inhibitors (Science 2003) in animal models of PD confirm a role for TNF in DA neuron loss (J Neuroscience, in press) and raise the exciting possibility that anti-TNF therapy could be used in humans to prevent or attenuate the progressive loss of these neurons characteristic of PD. These important findings have led us to embark upon development of new chronic progressive predictive 'second hit' models of PD in collaboration with the Goldberg lab in Neurology which created mice deficient for genes shown to be involved in development of familial forms of PD. The long-term goal is to model earlier stages of PD in rodents so we can then use these models to test new compounds for neuroprotective or neurorestorative activity which can quickly be moved into the clinic. DN-TNF inhibitors are scheduled to begin Phase I trials in patients with rheumatoid arthritis and we plan to investigate their use in PD.
Several projects are available in the Tansey lab to investigate the biochemical, neurohistological and behavioral outcomes in animal models of PD after exposure to chronic inflammatory stimuli.
Other available projects include:
-testing the hypothesis that the ratio of expression of TNFR1 (a canonical death receptor) to TNFR2 (an NFkB-linked receptor) in different neuron types critically determines the functional outcome of a TNF stimulus in the brain (neuroprotective versus neurotoxic) using in situ hybridization, immunohistological, and laser-capture/QPCR techniques.
- test the hypothesis that microglial phenotypes (neurotoxic versus neuroprotective) are modulated by TNF via upregulation and downregulation of specific cell surface markers on brain microglia and specific RGS proteins that regulate phagocytosis and respiratory (ROS/RNS) bursts in these cell types by using a combination of FACS sorting, immunostaining, and real-time QPCR techniques.
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