Leptin signaling and RNA m6A methylation in acute lung injury: pathways to microvascular barrier protection and therapeutic targets – LAMPS

Acute respiratory distress syndrome (ARDS) is a complex and severe syndrome characterized by an acute lung injury (ALI) without curative treatments. Disruption of lung microvascular barrier and dysregulated inflammation are the central pathophysiological features of ALI common to all ARDS etiologies but the underlying mechanisms are not completely understood. Robust preliminary data and expertise from both partners indicate that leptin pathway may play a physiopathological role on the integrity of the pulmonary microvascular barrier, possibly through post-transcriptional RNA methylation of adenosine at the 6th nitrogen position (m6A) modifications. The overall goal of this proposal is to explore the interplay between leptin signaling and alterations in the RNA m6A machinery in the lung, and how these interactions influence the integrity and function of the lung microvascular barrier in ALI. Using a combination of in vivo, in situ, ex vivo and in vitro approaches, as well as transgenic mice models, our complementary expertise will aid to uncover novel therapeutic targets that could restore proper lung microvascular barrier homeostasis, ultimately improving patient outcomes and reducing the burden of this devastating condition. After coronavirus disease (COVID)-19 pandemic, it appears clearly that there is an urgent need for curative therapies that can restore the integrity of the alveolar-capillary barrier in ALI. Our interdisciplinary proposal has strong preliminary results and several innovative features both conceptual and technological, that are crucial to better understand ALI pathophysiology and are the key to this proposal feasibility and success, in order to develop innovative targeted ARDS therapies and improve patient survival and care.