In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The journal accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
Vitamin A and its active metabolite retinoic acid (RA) are essential for lung formation, though it is not clear if prenatal vitamin A deficiency influences postnatal lung development and function. In this episode, Wellington Cardoso provides evidence that prenatal disruption of RA signaling results in aberrant, overly differentiated smooth muscle in airways. RA deficiency-associated defects persisted, regardless of the adult vitamin A status, and manifested in airway hyperresponsiveness and structural changes in the bronchial smooth muscle. The study indicates that RA signaling in the developing lung prevents excessive smooth muscle formation.
Nonsense mutations that lead to PAX6 haploinsufficiency cause congenital aniridia, a panocular condition that results in severe vision defects. Cheryl Gregory-Evans and colleagues hypothesized that suppression of nonsense mutations could increase PAX6 levels and prevent post-natal eye damage. They developed a topical formulation of ataluren that not only inhibited disease progression, but also reversed ocular malformations and restored retinal responses in Pax6-deficient mice.
In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.
Damage to the glomerulus, which mediates the kidney's filtering function, causes plasma protein to spill into the urine, a sign of kidney failure and cardiovascular disease. Calcium influx into the podocytes, the cells that form the filtration barrier of the glomerulus, is known to damage the glomerulus, but the ion channel that mediates this influx was unknown. In this episode, Anna Greka and colleagues discuss their recent work demonstrating that inhibition of the TRPC5 ion channel protects mice from kidney damage by preventing calcium influx into the podocytes, and blocks the cytoskeletal alterations in the podocytes that disrupts the filtration barrier in the glomerulus.
Results from early-phase clinical trials have indicated that recombinant adeno-associated viruses (rAAV) could potentially be used for gene therapy. In each trial, however, patients have developed T cell-mediated immune responses that may interfere with therapeutic gene expression. In this episode, Terence Flotte and Christian Mueller discuss their recent study investigating T cell responses to intramuscular injection of a rAAV encoding M-type a1-antitrypsin (AAT) in patients with AAT-deficiency. Their results demonstrate that AAT expression persists for up to 12 months and suggest that immunomodulation of T cell populations may not be necessary for long-term, rAAV-mediated transgene expression.