Lauren Shechtman

UC San Francisco

“Rasgrp1 promotes fitness of the intestinal epithelium in response to injury”

The continuous balance between ISC renewal, differentiation, and apoptosis, renders the small intestine readily prone to perturbation; interestingly, preliminary data observed in the Roose lab of a genetically engineered mouse model has revealed a phenotype wherein the intestinal epithelium is severely perturbed, and mouse survival rates significantly decline. I therefore aim to use mouse models and organoid technology to elucidate whether this phenotype is the consequence of a dysfunction in ISC regenerative capacity, or a decline in ISC niche fitness.


The abrasive environment of the small intestine (SI) requires constant renewal of differentiated cells, which are persistently replenished by intestinal stem cells (ISCs). Intriguingly, short-term ablation of undifferentiated ISCs in mice doesn’t disrupt homeostasis. Growing evidence proposes that various cell populations in the SI can de-differentiate and replenish ISCs during injury. However, it is unclear what molecular mechanisms govern this regenerative property of the intestine. Stem cell fate decisions are dependent on tight regulation of protein synthesis. Mammalian target of rapamycin (mTOR) is a critical coordinator of protein synthesis and mTOR signals are regulated by Rasgrp1 (Ras guanyl nucleotide releasing protein 1). Specifically, Rasgrp1/mTOR signals have been implicated to drive translational activity, promoting cell fitness. In the intestine, Rasgrp1 seems dispensable during homeostasis. However, upon injury, deletion of Rasgrp1 results in a decrease in mouse survival rates. Thus, I propose Rasgrp1 promotes fitness of the SI and drives replenishment of ISCs upon injury via mTOR signals/protein synthesis. To test this, I will use mouse genetics, single-cell sequencing, and an established small-intestine organoid system.

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