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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of cognitive impairment in older persons. AD is characterized by a gradual and progressive decline in memory and other cognitive functions, including language skills, the recognition of faces and objects, the performance of routine tasks, and executive functions. Additionally, AD places a terrible burden on primary family caregivers, about half of whom become clinically depressed. AD afflicts about 10% of those over the age of 65 and almost half of those over the age of 85. By 2050, the prevalence of AD in the United States alone is projected to increase from about 4 to 16 million cases and the annual cost of the disorder is projected to increase from about 188 to 752 billion dollars per year. AD treatments and prevention therapies are needed to avert a catastrophic public health problem. At the cellular level, AD is characterized pathologically by amyloid plaques and neurofibrillary tangles (NFT). Genetic and molecular experiments have linked amyloid pathology, NFTs, and neurodegeneration. However, NFTs can occur without concomitant amyloid pathology in a broad class of neurodegenerative diseases, collectively known as “tauopathies.” This indicates that NFTs themselves are intricately involved in neurodegenerative processes. Despite the central role of neurofibrillary tangle formation to the pathogenesis of AD, little is known about the molecular events leading to the fibrillar aggregation of tau, the predominant protein component of NFTs. I am specifically interested in identifying these molecular events that lead to the formation of neurodegenerative NFTs and subsequently developing novel therapeutics to target those genes, with the goal of blocking or slowing neurodegeneration. Our novel approach to studying this currently intractable and fatal disorder is to identify the entire set of genes that contribute to NFT formation through the combination of state-of-the-art genomic and proteomic technologies to directly identify the relevant neuron-specific genes responsible for the development of NFTs and subsequent neurodegeneration. Information about the genes that are differentially expressed in neurons containing neurofibrillary tangles relative to histopathologically normal neurons and functional validation of those differences will greatly increase our understanding of the molecular mechanisms involved in the development of this dementia-inducing form of pathology. In addition, knowledge of the cellular signaling pathways that are affected during neurofibrillary tangle formation may provide novel targets for the discovery of interventions to treat and prevent tangle-induced dementia. Importantly, understanding the molecular basis for neurofibrillary tangle formation may be generally applicable to the treatment of other neurodegenerative tauopathies, such as progressive supranuclear palsy, Pick’s disease, and corticobasal degeneration.
Dr. Dunckley obtained his undergraduate degree in molecular and cellular biology and biochemistry from the University of Arizona. His doctoral work was completed at the University of Arizona in the field of molecular and cellular biology. Prior to joining TGen, he studied gene expression at the level of mRNA stability. In 2000, Dr. Dunckley expanded his training to the field of Neurobiology during a fellowship position at Barrow Neurological Institute. While there he investigated structure/function interactions in nicotinic acetylcholine receptors (nAChR) and identified novel genes regulated by nAChR activity. In 2003 he transitioned to the Neurogenomics division at TGen where he is currently applying genomic techniques toward clinically meaningful scientific advances in neurodegenerative diseases, with a specific focus on AD and Parkinson's disease.
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