RET Signaling Persists in the Adult Intestine and Stimulates Motility by Limiting PYY Release From Enteroendocrine Cells.

BACKGROUND & AIMS: RET tyrosine kinase is necessary for enteric nervous system development. Loss-of-function RET mutations cause Hirschsprung disease (HSCR), in which infants are born with aganglionic bowel. Despite surgical correction, patients with HSCR often experience chronic defecatory dysfunction and enterocolitis, suggesting that RET is important after development. To test this hypothesis, we determined the location of postnatal RET and its significance in gastrointestinal (GI) motility. METHODS: RetCFP/+ mice and human transcriptional profiling data were studied to identify the enteric neuronal and epithelial cells that express RET. To determine whether RET regulates gut motility in vivo, genetic, and pharmacologic approaches were used to disrupt RET in all RET-expressing cells, a subset of enteric neurons, or intestinal epithelial cells. RESULTS: Distinct subsets of enteric neurons and enteroendocrine cells expressed RET in the adult intestine. RET disruption in the epithelium, rather than in enteric neurons, slowed GI motility selectively in male mice. RET kinase inhibition phenocopied this effect. Most RET+ epithelial cells were either enterochromaffin cells that release serotonin or L-cells that release peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), both of which can alter motility. RET kinase inhibition exaggerated PYY and GLP-1 release in a nutrient-dependent manner without altering serotonin secretion in mice and human organoids. PYY receptor blockade rescued dysmotility in mice lacking epithelial RET. CONCLUSIONS: RET signaling normally limits nutrient-dependent peptide release from L-cells and this activity is necessary for normal intestinal motility in male mice. These effects could contribute to dysmotility in HSCR, which predominantly affects males, and uncovers a mechanism that could be targeted to treat post-prandial GI dysfunction.

Association of Surgeon Representation on NIH Study Sections With Receipt of Funding by Surgeon-scientists.

OBJECTIVE: Our goal was to evaluate the relationship between surgeon representation on NIH study sections and success in grant funding. SUMMARY OF BACKGROUND DATA: NIH funding for surgeon-scientists is declining. Prior work has called for increased surgeon participation in the grant review process as a strategy to increase receipt of funding by surgeon-scientists. METHODS: A retrospective review of surgeon (primary department: General, Urology, Orthopedic, Ophthalmology, Otolaryngology, Neurosurgery) representation on NIH study sections and receipt of funding was performed using NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) and 2019 Blue Ridge Institute for Medical Research data. NIH chartered study section panels and ad hoc reviewers for each 2019 review date were also obtained. RESULTS: In 2019, 9239 individuals reviewed in at least 1 of the 168 study sections [190 (2.1%) surgeons, 64 (0.7%) standing members, 126 (1.4%) ad-hoc]. Most surgeons on study sections were male (65%) professors (63%). Surgeons most commonly served on bioengineering, technology, and surgical sciences (29.6% surgeons), diseases and pathophysiology of the visual system (28.3%), and surgery, anesthesiology and trauma (21%). In 2019, 773 surgeons received 1235 NIH grants (>$580 M) out of a total of 55,012 awards (2.2%). Funded surgeons were predominantly male (79%), White (68%), non-Hispanic (97%), full professors (50%), and 43% had additional advanced degrees (MPH/PhD/MBA). surgery, anesthesiology and trauma, diseases and pathophysiology of the visual system, and bioengineering, technology, and surgical sciences were the most common study sections that reviewed funded grants to surgeon-scientists. Ninety-two surgeons both received grant funding and served on study section. Study sections with higher surgeon representation were more likely to fund surgeon-scientists (P < 0.001). CONCLUSIONS: Surgeon representation on NIH study sections is strongly associated with receipt of funding by surgeon-scientists. Increasing NIH study section representation by surgeons may help to preserve the surgeon-scientist phenotype.