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.
The development of atherosclerotic plaques typically occurs in regions of arteries that have disturbed blood flow. While blood flow disturbances are known to alter endothelial gene expression and function, it is not clear how altered blood flow induces these changes. In this episode, Hanjoong Jo presents evidence that blood flow disturbances alter genome-wide methylation patterns in endothelial cells through induction of the DNA methyltransferase DNMT. Long-term epigenetic changes induced within the arterial endothelium may lead to development of atherosclerosis, and genes that are altered in response to disturbed flow represent potential therapeutic targets for limiting plaque formation.
Capillary malformation-arteriovenous malformation (CM-AVM) results from inactivating mutations in the gene encoding RAS p21 protein activator (RASA1); however, RASA1 is expressed in multiple tissues, and it is not clear how RASA1 mutations promote vascular dysfunction. Joanne Chan and colleagues determined that loss of either the receptor EPHB4, a regulator of vascular development, or RASA1 induces similar abnormalities in blood vessel formation and TORC1 hyperactivation in zebrafish models. Increased mTORC1 activation was detected in samples from patients with RASA1-dependent AVM, suggesting that currently approved therapeutics targeting mTORC1 could potentially be used to treat CM-AVM.
Induction of type I interferon (IFN) signaling is critical for host defense against most viruses; however, for some pathogens, including the parasite that causes malaria, induction of type I IFN-mediated pathways enhances host susceptibility to disease. In this episode, Ashraful Haque discusses results from a collaboration with Christian Engwerda that demonstrates pathogen-dependent type I IFN responses in a murine model of severe malaria inhibit the ability of conventional dendritic cells (cDCs) to promote Th1-mediated immunity. The results from this study suggest that limiting type I IFN signaling in cDCs could enhance long-term protection against malaria and other pathogens that promote type I IFN signaling.
Chronic itch is a common symptom and complaint for many dermatological patients. While some patients find relief with antihistamines, many do not, and the underlying pathways responsible for itch are poorly understood. In this episode, Martin Steinhoff details the identification of endothelin–converting enzyme 1 (ECE-1) as a key regulator of endothelin (ET-1), which evokes a histamine-independent pruritus through activation of ERK1/2. In murine itch models, scratching behavior was enhanced by pharmacological inhibition of ECE-1 and ameliorated by administration of an ERK1/2 inhibitor. Furthermore, this ECE-1/ER-1/ERK1/2 axis was upregulated in patients with prurigo nodularis, suggesting that this pathway has potential as a therapeutic target to relieve chronic itch.
Broadly neutralizing antibodies (BnAbs) represent a promising strategy for targeting rapidly mutating viruses, such as HIV-1. BnAbs recognize conserved epitopes and display unique characteristics that suggest that their development may be limited by immune tolerance. In this episode, Baton Haynes discusses the identification and characterization of a BnAb in an HIV-1-infected individual that developed the autoimmune disease systemic lupus erythematosus. The BnAb targeted both the HIV-1 envelope and human antigens, including dsDNA, supporting the hypothesis that lax immune control allows for maturation and production of BnAbs.