Sunday, November 24, 2024
11/24/2024
Summary Endothelial barrier dysfunction (EBD) has been associated with crucial lung injury ((e.g. acute respiratory distress syndrome (ARDS)) and deaths in the Intensive Care Units. Approved medicine that specifically targets EBD does not exist, hence the development of efficient medical countermeasures in that context is of the utmost need. Synthetic somatostatin analogs (SSAs) suppress the secretion of growth hormone (GH), are FDA-approved, and are currently used in clinics for the treatment of acromegaly and neuroendocrine neoplasms. This R03 proposal is based on the concept that SSAs protect against EBD. If our hypothesis is proven correct, SSAs can be eventually tested against the corresponding disorders. Based on preliminary observations, we will pursue Specific Aim 1 to investigate the role of Lanreotide (LAN), Octreotide (OCT) and Pasireotide (PAS) in LPS- and IFNγ -induced EBD. To do so, we will utilize human lung microvascular endothelial cells, post-treated with SSAs after LPS or IFNγ exposure, to assess their effects in transcellular and paracellular permeability, cell injury and inflammation. Unfolded Protein Response (UPR) is a homeostatic signaling network activated upon increases of endoplasmic reticulum (ER) stress, and it is involved in the regulation of endothelial barrier function. Global UPR induction counteracts Kifunensine (UPR suppressor)-triggered EBD. Our preliminary observations suggest that LAN induces BiP-a UPR activation marker- and activates ATF6, which has been shown to deliver protection in experimental models of widespread disease. To further our studies, we selectively suppressed ATF6 in endothelial cells to reveal that targeted ATF6 suppression potentiates LPS-induced EBD. Based on our published and unpublished observations, we will assess Specific Aim 2, to examine the involvement of ATF6 in the protective effects of SSAs in EBD. We will test the effects of SSAs in inflamed endothelial cells that express more or less of ATF6, in the context of injury and barrier function. New preliminary data suggest that LAN and OCT oppose LPS- induced acute lung injury (ALI) in mice. Based on those observations, New Specific Aim 3 will further our knowledge on the effects of SSAs in a murine model of LPS-induced ALI, and in the context of ATF6. The completion of our studies will reveal a novel avenue of investigation, based on the SSAs application in disorders related to EBD. All necessary material is commercially available, and alternative approaches have been developed to cover most of the possible outcomes. To the best of our knowledge, thorough studies on the effects of SSAs in EBD - and in the context of ATF6 - have not been conducted, yet.
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