Pharmaceutical Sciences Research Opportunities

Christine Dengler-Crish, Ph.D.

Disease-related Changes in the Distribution of Cell-Surface Integrins in Brain of Alzheimer’s Model Mice

A major goal of our laboratory is to understand some of the earliest pathological mechanisms that contribute to Alzheimer’s brain pathology. Decades prior to the first signs of cognitive deficits, tau pathology begins to accumulate in the brain, yet in fully symptomatic disease stages, spread of brain tauopathy closely correlates with progression of cognitive decline. There is a critical need to understand the factors fueling progression of tauopathy across these disease stages, and this defines the overall purpose of our research to identify early disease mechanisms that can be targeted to prevent onset of dementia.

A potential contributor to tauopathy progression involves the dysfunctional signaling of cell surface integrins. In the healthy adult brain, integrins are expressed ubiquitously and play important roles in neural plasticity. Recent studies have suggested that changes in expression levels and function of specific integrin subtypes may be associated with onset and spread of Alzheimer’s brain pathology. Our lab has preliminary data showing that αVβ integrins (which are shown to directly bind tau) are dramatically upregulated in hippocampus of transgenic tauopathy model (htau) mice, and this increase occurred over a 5 month period as these animals aged from presymptomatic (5mo.) to symptomatic ages (10 mo.). The proposed project will work to determine which specific integrin subtypes (αVβ1, αVβ3, αVβ5, αVβ6 or αVβ8) are differentially regulated in htau mouse hippocampus and brainstem across disease stage and sex. Student fellows will be expected to work with brain tissue obtained from htau mice to conduct immunofluorescence assays to label αV integrin subtypes in target brain regions, and use microscopy to image and quantify integrin subtypes.

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Sheila Fleming, Ph.D.

Gene-Environment Interactions in Parkinson’s Disease

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra and the development of lewy bodies and lewy neurites in the brain and periphery. While the cause of the majority of cases is unknown, it is generally considered that gene-environment interactions underlie most cases of PD. Therefore, the identification of gene-environment interactions associated with PD-like pathology and neurodegeneration is an important goal in the field. ATP13A2 is a P₅-ATPase of the P-type ion transport ATPase superfamily and loss of function mutations cause the neurodegenerative condition Kufor-Rakeb Syndrome, an autosomal recessive form of PD. The function of ATP12A2 is unclear but in vitro studies suggest it may be involved in the lysosomal degradation of proteins, polyamine and heavy metal transport (manganese and/or zinc), and mitochondrial function, all mechanisms that can overlap with PD. An important next step is to determine how loss of function of ATP13A2 in vivo interacts with environmental factors such as heavy metals and toxicants that interfere with cellular transport, protein degradation, and mitochondrial function.   It is hypothesized the loss of ATP13A2 function causes an increased vulnerability to the toxic effects of certain heavy metals and pesticides associated with PD. This hypothesis will be tested using Atp13a2-deficient mice that have been shown to develop age-dependent motor impairments, enhanced accumulation of lysosomal storage material, and increased accumulation of the PD protein alpha-synuclein. Wildtype and Atp13a2-deficient mice will be exposed to different metals and toxicants associated with PD (ex. manganese). Sensorimotor function will be measured and in the brain accumulation of the PD protein alpha-synuclein and neurodegeneration will be determined. A combination of behavioral, cellular, and molecular techniques will be employed.

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Woo Shik Shin, Ph.D.

Novel Combination Antibacterial Therapy Against Carbapenem-Resistant Acinetobacter Baumannii

Carbapenem-resistant Acinetobacter baumannii (CRAb) is an urgent public health threat, according to the CDC. This pathogen has few treatment options and causes severe nosocomial infections with >50% fatality rate. Since more than five decades ago, β-lactam class antibiotics have been the primary therapeutic treatment used to combat both gram-positive and negative bacterial infections. However, the emergence of β-lactam drug resistance bacterial pathogens has become a major public health threat against immune-compromised individuals, post-surgical patients, and the elderly in hospitals. The major goal of the project is to develop a novel class of potent β-lactamase inhibitors to rescue existing β-lactam antibiotic activities for combination antibacterial therapy. The ability to preserve the efficacy of existing β-lactam antibiotics arsenal provides maximum opportunity for combination antimicrobial therapy development. To achieve this objective, we will use a state-of-the-art drug design methodology involving computational molecular modeling, cell/enzyme-based study, and chemical synthesis to generate inhibitors of a β-lactamase protein. Estimating first-time novel class of compounds as potent irreversible/reversible inhibitors against β-lactamase with low micromolar inhibition activities comparable to established FDA approved β-lactamase inhibitors drugs.

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