Key Words

Bcl-xL and delta-N-Bcl-xL

Mitochondria

ATP

Neuronal growth and development

Neuronal death (apoptosis)

Excitotoxicity

Oxidative stress and antioxidants

Hippocampus

Learning and memory

Anxiety and stress

Aging

Neurodegenerative diseases (Parkinson’s and Alzheimer’s)

Cerebral ischemia

Research Topics

1. Mechanisms of hippocampal loss and cognitive impairment

    The hippocampus is a central structure in the brain and has a major role in learning and memory.  Hippocampal damage caused by stroke (Figure 1), aging, or neurodegenerative diseases like Alzheimer’s is associated with cognitive impairment.   We investigate molecular mechanisms of hippocampal damage and develop strategies to improve hippocampus-dependent cognitive functions using genetic, pharmacological, and nutritional interventions.

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Figure 1. 4VO-induced global ischemia causes loss of CA1 hippocampal neurons in rats.  NeuN positive CA1 hipocampal neurons are decreased at 7 days post-4VO in rats. A, Sharm. B, 4VO.                                                                                                                              

2. Mechanisms of Bcl-xL depletion or ΔN-Bcl-xL accumulation during pathological processes in the brain

    B-cell lymphoma-extra large (Bcl-xL) is a anti-apoptotic protein localized to mitochondria. Bcl-xL improves neuronal ATP production supporting neurite outgrowth (Figure 2) and neuronal survival.  In contrast to its protective role, Bcl-xL also plays a major role in neuronal death when Bcl-xL undergoes caspase 3-dependent N-terminal cleavage to form ΔN-Bcl-xL.   We investigate molecular mechanisms of ΔN-Bcl-xL/Bcl-xL balance (e.g. Bcl-xL depletion and ΔN-Bcl-xL accumulation) during pathological processes in the brain such as cerebral stroke, aging, and neurodegenerative diseases.

Figure 2. Depletion of Bcl-xL alters morphology of neurites. A, A lenti-control CopGFP transduced hippocampal neuron. B, A lenti-Bcl-xL-shRNA-GFP transduced hippocampal neuron.          

3. Mechanisms of mitochondrial recruitment during normal physiology and during recovery after neurotoxic stimulation

 

     Neurite extension and synapse formation require abundant ATP. Therefore, maintaining a healthy population of mitochondria, the ATP producing organelle of the cell, at the growing sites of neurites is critical to preventing neuronal loss during stroke, aging, and neurodegenerative disease.   We study mechanisms of mitochondrial docking, distribution, and mobility (Figure 3).  We also investigate mitochondrial availability and neurite outgrowth during normal development and during recovery after brain injury.

Figure 3. Movement of mitoRED labeled- mitochondria in hippocampal neurites.          

4. Strategies to inhibit neuronal death signaling via nutrition-based interventions

    The approaches used to date to experimentally prevent neuronal damage or to promote neuronal survival have limitations (e.g. safety and availability) in translation to human subjects.  Therefore, we investigate readily-applicable strategies to protect the human brain.  We test whether nutrients, food-based compounds with minimal side effects, are capable of regulating activity of target proteins by 1) direct binding (Figure 4), 2) epigenetic control of transcription and translation,  3) intervening on neuronal death signaling pathways.  The ultimate goal of this project is to determine whether nutritional intervention can delay neuronal death and promote rehabilitation of the brain.

Figure 4. Model of ΔN-Bcl-xL-vitamin E complex.

Docking of α-TCT (grey) to the crystal structure of ΔN-Bcl-xL.   

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