In recent years, I have focused my research on neurodegeneration, specifically Alzheimer’s disease (AD). Physiologically, AD involves damage to brain cells and their eventual death. It is a progressive and irreversible disorder with no identifiable treatment or real understanding of the mechanisms and molecular determinants involved in the disease process. A majority of the destruction that occurs in AD takes place in parts of the brain that are vital for memory, such as the cortex. In addition, AD is characterized by additional changes in the brain. These include the formation of tangles and plaques composed of Tau and Beta-amyloid protein, respectively. By the time symptoms occur for AD, these physiological changes have started to occur in
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As a post-doctoral fellow, I identified a new regulator that linked cell death (apoptosis) and neurodegeneration with circadian regulation. Apoptosis is an important physiological mechanism by which a single cell is eliminated from living tissue and plays an essential role during development and homeostasis of adult tissues. Therefore, deregulation of apoptosis is frequently associated with diseases ranging from cancer to neurodegeneration. In humans, aging is often associated with reduced function of the circadian clock and increased incidence of neurodegeneration, but the mechanism that links reduced circadian function and increased neurodegeneration is not known. Our results suggest that the circadian kinase, Casein kinase I, inhibits the activation of caspases to prevent Tau cleavage, and that the defects in the circadian clock confer sensitivity to expression of active caspase in response to prolonged light. We establish a link between the circadian clock factors, light, cell death pathways, and Tau toxicity. I continued my work on neurodegenerative processes as a Senior Research Scientist using mammalian …show more content…
Calcium serves a vital role in the physiological functional regulation of the central nervous system and disruption of calcium signaling in neurons is a major factor that is frequently present with a number of features of AD. The increase in intracellular calcium levels are linked to amyloid plaques and Tau tangles. This increase in calcium levels along with oxidative stress has been implicated in AD pathogenesis. In AD brains, calcium levels are abnormal, and this leads to caspase activation and eventual Tau cleavage. I am currently investigating the role that the calcium receptors have in disease onset and progression. Initial data from our plate reader assays and whole brain and single-cell calcium imaging show that overexpression of the calcium receptor, IP3R increased the severity of calcium overloading-induced neuronal cell death, which was mediated by the caspase apoptotic pathway. In addition Tau associates with IP3R and when Tau is added to neuronal cells an increase in intracellular calcium (likely from the activation of the ER-calcium IP3Rs) is observed. There is evidence for ER calcium stores dysfunction in AD. This dysfunction has been related to Beta-amyloid pathology, but the modulation of IP3R by pathology related to Tau has not been reported. Our results suggest that downregulating IP3R expression or
As a post-doctoral fellow, I identified a new regulator that linked cell death (apoptosis) and neurodegeneration with circadian regulation. Apoptosis is an important physiological mechanism by which a single cell is eliminated from living tissue and plays an essential role during development and homeostasis of adult tissues. Therefore, deregulation of apoptosis is frequently associated with diseases ranging from cancer to neurodegeneration. In humans, aging is often associated with reduced function of the circadian clock and increased incidence of neurodegeneration, but the mechanism that links reduced circadian function and increased neurodegeneration is not known. Our results suggest that the circadian kinase, Casein kinase I, inhibits the activation of caspases to prevent Tau cleavage, and that the defects in the circadian clock confer sensitivity to expression of active caspase in response to prolonged light. We establish a link between the circadian clock factors, light, cell death pathways, and Tau toxicity. I continued my work on neurodegenerative processes as a Senior Research Scientist using mammalian …show more content…
Calcium serves a vital role in the physiological functional regulation of the central nervous system and disruption of calcium signaling in neurons is a major factor that is frequently present with a number of features of AD. The increase in intracellular calcium levels are linked to amyloid plaques and Tau tangles. This increase in calcium levels along with oxidative stress has been implicated in AD pathogenesis. In AD brains, calcium levels are abnormal, and this leads to caspase activation and eventual Tau cleavage. I am currently investigating the role that the calcium receptors have in disease onset and progression. Initial data from our plate reader assays and whole brain and single-cell calcium imaging show that overexpression of the calcium receptor, IP3R increased the severity of calcium overloading-induced neuronal cell death, which was mediated by the caspase apoptotic pathway. In addition Tau associates with IP3R and when Tau is added to neuronal cells an increase in intracellular calcium (likely from the activation of the ER-calcium IP3Rs) is observed. There is evidence for ER calcium stores dysfunction in AD. This dysfunction has been related to Beta-amyloid pathology, but the modulation of IP3R by pathology related to Tau has not been reported. Our results suggest that downregulating IP3R expression or