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Nicholas Maragkis, MD, PhD

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Nicholas Maragkis, MD, PhD

Johns Hopkins University

Investigating the contributions of astrocyte gap junctions to ALS disease progression

Previous work has shown that astrocytes and other glia are involved in ALS disease pathobiology, particularly disease progression after onset. We propose that gap junctions (intercellular channels that directly connect the cytoplasms of different cells) in astrocytes contribute to the progression of ALS over time and its spread to neighboring cells. We will also utilize our experience in culturing and differentiating human iPS cells from ALS subjects into astrocytes (and neurons) to allow for the in vitro analysis of functional gap junction biology. Finally, we will utilize an ALS mouse model that we have derived by crossing the SOD1G93A mouse with knockout mice lacking the gap junction protein connexin 43 that will allow for an in vivo extrapolation of our in vitro findings to elucidate the importance of this Cx43 upregulation. This will be accompanied by the use of shRNA strategies to focally knockdown Cx43 and examine both the potential for neuroprotection as well as the reduction of contiguous disease spread along the axis of the central nervous system.

 

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Steven Finkbeiner

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Gladstone Institutes, UCSF
Two recently discovered genes that have been associated with both familial and sporadic forms of ALS encode the related proteins TDP43 and FUS cause neuron death in ALS.
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