Grant: Doctoral: Anne Martin-Matthews Prize of Excellence on Aging

The process of aging involves cell division and a subsequent shortening of telomeres - protein-DNA complexes that "cap" ends of chromosomes. Telomeres contribute to chromosome stability, and critically shortened telomeres are "uncapped," setting off a DNA damage response and results in programmed cell death (apoptosis) or cell cycle arrest (senescence). Telomerase, present in many stem cells, is a protein-RNA complex that elongates telomeres. We study a mouse model lacking the RNA component of telomerase (TR), which exhibits telomere shortening across all tissues. One of the main pathologies that emerges is within the gastrointestinal (GI) epithelium. Physiologically, these mutant mice waste away compared to their wild-type littermates. Histologically, the mutant intestines exhibit morphologic distortion, inflammation, and increased telomere uncapping and apoptosis in intestinal crypts, where intestinal stem cells (ISCs) are located. The observed pathology is similar to human inflammatory bowel disease and some aging-related GI disorders. We found that the expression of stem cell-specific genes under the control of the Wnt pathway are diminished in the TR mutants. Remarkably, pathology and stem cell gene expression in mutant mice are rescued by bone marrow transplant from wild-type donors, despite the fact that donor-derived cells do not contribute directly to the epithelia of the recipients. We hypothesized that the rescue was mediated by the Wnt pathway, and we have indeed recapitulated the rescue using short-term pharmacologic treatment with Wnt pathway agonists. Stimulating the Wnt pathway resulted in decreased apoptosis and improved telomere capping in the ISCs, improving overall GI health. We will explore the hypothesis that Wnt signaling improves telomere capping by upregulating key capping proteins. Understanding how Wnt signaling promotes telomere function in ISC biology holds promise for developing therapies for GI and aging-related diseases.