Malú G. Tansey
Associate Professor of Physiology
Ph.D., University of Texas Southwestern, 1992
Our main research interests include cellular and molecular mechanisms involved in regulation of glial activities and neuronal survival by Tumor Necrosis Factor (TNF) and Regulator of G-protein Signaling-10 (RGS10). We aim to identify TNF-dependent signal transduction cascades and their molecular regulators underlying neuroinflammatory stress responses that compromise neuronal survival and/or promote neuronal apoptosis in cell-based and animal models of neurodegeneration. We employ molecular, cellular, biochemical, pharmacological, immunohistological, fixed and live-cell high-content imaging, and behavioral assays to address important mechanistic questions with the long-term goal of developing novel therapeutics for the prevention and/or treatment of chronic neurodegenerative diseases characterized by chronic neuroinflammation, in particular, Parkinson's disease (PD).
1. Mechanisms of TNF-dependent neuroinflammation and neurotoxicity and their role in etiology and progression of Parkinson's Disease (PD).
A wealth of evidence arising from PET imaging studies, human autopsy samples, and animal models reveals massive astrogliosis, the presence of activated microglial cells, and elevated levels of inflammatory cytokines, including TNF, in brain regions most affected by the disease. In addition, epidemiological studies suggest that chronic use of NSAIDs lowers the risk for developing idiopathic/sporadic PD, suggesting that inflammation may be contributing to neurodegeneration. We use novel engineered dominant-negative TNF inhibitors (McCoy et al., 2006), viral vectors encoding DN-TNF sequences (McCoy et al., 2008; McAlpine et al., 2009; Harms et al., 2010), and other anti-inflammatory compounds (Tran et al., 2008) as tools to selectively target specific mediators (solTNF, NFkB, etc.) to investigate their role and signaling pathways via which they impact neuronal function and survival of in vitro and in vivo. Our translational research efforts are aimed at identifying the neuroinflammatory and neurotoxic mechanisms that promote neuronal degeneration and death with the long-term goal of developing therapeutic strategies to protect vulnerable neuronal populations and delay or prevent onset of neurodegenerative diseases like PD. Funding for these projects comes from the Michael J. Fox Foundation of Parkinson's Research and the NIH/NINDS.
2. Role of Regulator of G-protein Signaling-10 (RGS10) in microglia activation, innate immunity, and dopaminergic neuron survival.
3. Gene-environment interactions in the etiology of idiopathic neurodegenerative diseases.
We have a long-standing interest in the interplay between genetic susceptibility and environmental factors now recognized to underlie the etiology of idiopathic neurodegenerative diseases. As such, we seek to develop 'second-hit' mouse models of disease in which a genetic deficiency is combined with an environmental stressor or exposure to investigate the function of a particular pathway in conferring susceptibility or protection against a specific stressor. Using this approach, we have discovered a role for Parkin in protection against systemic inflammation-related degeneration (Frank-Cannon et al., 2008). The long-term goal of these studies is to establish the extent to which various environmental factors (including psychological stress, peripheral inflammation, infections, and obesity) endemic in the U.S. population enhance neuroinflammation, compromise neuronal function and survival, and contribute to neurodegeneration and cognitive decline. Funding support for these studies comes from The Michael J. Fox Foundation for Parkinson's Research and the Parkinson's Disease Movement Foundation.4. Role of MHC-II in Neuro-immune Interactions and Neurodegenerative Disease.
Several single nucleotide polymorphisms (SNPs) in the gene cluster that encodes proteins that function in immune responses (antigen presentation) have been reported to be associated with susceptibility to late-onset Parkinson's disease (PD) in genome-wide association studies (GWAS). One of these SNPs (rs3129882 initially referred to as PARK18) is a common genetic variant located within an intron of the HLA-DRA gene. In collaboration with Drs. Jeremy Boss in the Immunology and Microbiology Department and Stewart Factor in the Movement Disorders Clinic at Emory University, we are conducting studies to elucidate the mechanism by which this particular SNP (rs3129882) is associated with risk for PD. We will examine the hypothesis that a high risk allele (GG) at rs3129882 confers exacerbated or diminished immune responses. To determine if this genetic marker of PD is indicative of differential or misregulated HLA-DR gene expression (and subsequent changes in immune responses), immune cells isolated from the blood of PD patients and healthy volunteers will be compared. Immune cells from these individuals will be examined for expression of their HLA genes and a direct correlation between HLA-DR gene expression and disease will be made. Additionally, we will seek to determine if rs3129882 is predictive of a novel gene regulatory element or mechanism by determining the genetic regulatory activity of the DNA surrounding this region and examining ways in which this activity could be controlled, including an analysis of the epigenetic (non-DNA coding) patterns of inheritance associated with this region. If the hypothesis that the high risk allele (GG) genotype is predictive of exacerbated immune responses to neuronal injury associated with PD is correct, then development of distinct and novel diagnostic procedures may be possible to help predict onset, susceptibility, and rate of progression of this disease. Funding for these projects comes from The Michael J. Fox Foundation for Parkinson's Research, Emory's Parkinson's Disease Collaborative Environmental Research Center (PD-CERC) and Emory's Udall Center of Excellence for Parkinson's Research funded by the NIH/NINDS.
Publications: PubMed search
Department of Physiology