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Effects of strain on gene transfer

Gene therapy is an important advancement with the potential to revolutionize clinical medicine. However, current technologies to deliver genes are not sufficient to make this a reality in patients under even optimum conditions, let alone under stresses associated with many disease states. Prolonged and even short-term exposure to mechanical ventilation can cause profound changes in the alveolar epithelium. We are trying to develop non-viral gene therapy approaches to treat the acutely injured lung. As such, we must understand the mechanisms of gene transfer in alveolar epithelial cells under conditions that mimic those found during lung injury and its management (i.e., ventilation). Mechanical stretch induces numerous biological responses in cells, including alterations in the cytoskeleton, activation of cell signaling pathways, and upregulation of transcription factors. Intriguingly, these responses are directly related to the process of gene delivery to cells and tissues: (click image for larger view)

Exogenous DNA, either viral or non-viral, must cross the plasma membrane into the cell, travel through the cytooplasm and the cytoskeletal networks, enter the nucleus, and be transcribed in order for gene therapy to be successful. Plasmids most likely utilize the cytoskeletal network for movement through the cytoplasm, and form complexes with transcription factors for their nuclear entry.



Because mechanical stress alters both the cytoskeleton and the levels and subcellular localization of many transcription factors, it is likely that mechanical strain could play a large role in gene delivery. Indeed, in preliminary studies we have observed that cyclic stretch greatly enhances gene delivery and expression in alveolar epithelial cells.

Click image for larger view

We hypothesize that the cytoskeletal reorganization and transcription factor activation induced by mechanical stretch stimulates the ability of exogenous DNA, once inside the cell, to travel through the cytoplasm and into the nucleus for gene expression. Although not a "physiologically" normal process, the interactions of exogenous DNA

with the host cell are vital to methods scientists use everyday and form the basis for the next paradigm of disease treatment: gene therapy. Because cyclic stretch of alveolar epithelial cells mimics the mechanical force induced by ventilators on the lung, we may ultimately extend our findings on stretch-induced increases in gene transfer to the lung in vivo to develop improved approaches for gene delivery.
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