Maternal B12 status influences offspring bone mass

The maternal environment not only affects in utero development, but also can dramatically influence postnatal phenotypes.  In this episode, Vijay Yadav, Isabel Quiros-Gonzalez, and Liesbet Lieben discuss their use of a murine genetic model to evaluate the effects of maternal vitamin B₁₂ deficiency on offspring bone formation. Pups from B₁₂-deficient mothers exhibited growth retardation and reduced bone mass due to a loss of taurine synthesis in the liver. Furthermore, administration of taurine to these offspring enhanced bone formation, ameliorating growth defects. The results from this study suggest that B₁₂/taurine supplementation may be a potential therapeutic strategy to increase bone mass.

Epigenetic consequences of disturbed blood flow

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.

Examining RASA1 in vascular malformation

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.

Dendritic cell-dependent inhibition of malaria immunity

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.

Neural peptidase regulates itch

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.