Oxygen is the terminal electron acceptor in the Electron Transport Chain of mitochondria. It is therefore needed to maximize energy and ATP production. Hypoxia is the condition of low oxygen levels. Hypoxia and the body’s response to hypoxia play a role in multiple human diseases, including ischemic stroke, myocardial infarction, hypertension, chronic kidney disease, COPD, and cancer. Understanding how tissues and cells respond to hypoxia is critical to the development of new therapeutic approaches for treating these diseases. It is also important to understand how diverse organisms evolved and adapted to hypoxic environments.

Questions About Hypoxia

How do cells sense hypoxia?

What are the factors that mediate a response to hypoxia?

Does hypoxia cause different effects in different types of tissue?

How does the hypoxic response operate holistically over multiple tissues?

What exactly is that response?

How does the response offset hypoxic damage?

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Mitochondria are the sites of oxygen respiration and energy production. More than just the “powerhouse of the cell,” they also mediate lipid metabolism, cytosolic calcium buffering, apoptosis, and necrosis. They are incredibly dynamic organelles that undergo fission, fusion, intracellular motility (transport), and multiple forms of quality control. Although mitochondria possess their own genome, most of the proteins that reside in mitochondria are encoded by the nuclear genome and must be imported across the double membrane structure of the mitochondria. Dysfunctional mitochondria play a role in multiple human diseases, including ischemic stroke, Parkinson’s Disease, Alzheimer’s Disease, ALS, Leigh Syndrome, optic atrophy, and cancer. Understanding how mitochondria function and are regulated in important for the development of new therapeutic approaches for treating these diseases.

Questions About Mitochondrial Dynamics

What mediates mitochondrial motility in complex cells like neurons?

How and why do mitochondria undergo fission and fusion?

How are nuclear-encoded proteins imported into mitochondria?

How are these mitochondrial dynamics regulated?

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Mitochondria are essential for cells that need to maximize ATP production. Neurons in the brain are particularly reliant on mitochondria for their energy needs, which are tremendous due to ATP required to maintain the electrochemical membrane potential that mediates neuronal communication. Yet, mitochondria are a potential threat to cells, as they produce free radicals and reactive oxygen species as byproduct of oxidative phosphorylation. The resulting oxidative stress can damage cell and result in neurodegeneration. Unlike many cells of the body, neurons are not easily replaced by stem cells and must survive with the risk of mitochondrial oxidative stress for decades. Neurons and other cells employ quality control mechanisms to offset potential damage from rogue mitochondria. One such mechanism is mitochondria-selective autophagy (mitophagy), which recognizes rogue mitochondria, engulfs them in augophagosomal membranes, and digests them following fusion with lysosomes. Failure to remove offensive mitochondria is associated with aspects of aging and diseases like Parkinson’s Disease.

Questions About Mitophagy

How do cells recognize a rogue mitochondria from a functional one?

What are the factors that mediate mitophagy?

How does mitophagy differ in different tissue types or during aging?

How is mitophagy regulated?

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Our studies of the hypoxia response pathway have recently focused on the pathways terminal effector: the transcription factor HIF-1. An ultimate goal in studying any signaling pathway that regulates gene expression at the transcriptional level is to identify and characterize all of the transcriptional targets of the pathway. To that end, we are using RNA-seq, ChIP-seq, and other Omics techniques to identify all of the target genes regulated by HIF-1. We are employing novel computational approaches to separate true targets from background noise and the technical artifacts that often arise when one uses these technical approaches. We are beginning to collaborate with other C. elegans researchers to use these same approaches to identify transcriptional targets of other interesting transcription factors and signal transduction pathways in the worm.

Questions About Transcription Factors

Where do transcription factors bind in the genome?

What computational tools can we use to identify their true regulatory targets?

How does the transcriptional profile activated by a signal transduction pathway change over time?

What is the relationship between transcription factor binding, the regulation of gene expression, and changes in the epigenetic chromatin landscape?

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