The inability of stem cells to support tissue homeostasis and repair underlies many age- related phenotypes. Specialized microenvironments called niches help maintain proper tissue homeostasis by controlling the balance between stem cell self-renewal and the differentiation of their daughters. However, the mechanisms that govern the formation, size and signaling output of in vivo niches remain poorly understood. Our long-term goal is to identify and characterize the factors that regulate niche function in vivo. Stem cells and their supportive microenvironments have often proven difficult to identify in vivo in many mammalian tissues. As a result, much of our current understanding of niches stems from the study of invertebrate models. In this proposal, we seek to build upon previous efforts that have established the Drosophila ovary as a powerful system with which to study stem cell niche aging. We propose to use state of the art cell purification and massive parallel sequencing techniques to systematically characterize the transcriptional profile of niche cells and their immediate neighbors. Moreover, we seek to genetically test the functional relevance of gene expression changes that occur within the niche during aging by using powerful cell-specific loss-of-function and gain-of- function techniques. We have established an operational pipeline for conducting all the experiments outlined under this proposal. Already, our preliminary data suggests that niches carry out previously unrecognized functions that are likely to be important for stem cell health and maintenance over time.
In Aim 1, we seek to comprehensively and quantitatively assess changes in gene expression within the Drosophila ovarian germline stem cell niche during aging.
In Aim 2, we will build upon our preliminary data and test whether niches help to protect stem cells from microbes that can be introduced through natural routes or via injury. Finally in Aim 3, we probe the molecular mechanisms by which a superoxide dismutase helps to prolong proper niche function late in life. We believe this comprehensive analysis of in vivo niche function during the course of aging will provide key insights into why stem cell activity declines with age and will reveal new molecular targets for the development of therapies designed to foster continued tissue homeostasis and regeneration in aging organisms.
Understanding the unique mechanisms that govern stem cell activity in vivo will have a positive impact on medical science. This proposal focuses on trying to characterize how the gene expression program of an in vivo stem cell niche changes with age using a powerful model system. We believe this work will reveal new and exciting principles in stem cell biology and will thus accelerate the development of new age-related therapies and the use of these cells in the treatment of human diseases.
| Inaba, Mayu; Yamashita, Yukiko M; Buszczak, Michael (2016) Keeping stem cells under control: New insights into the mechanisms that limit niche-stem cell signaling within the reproductive system. Mol Reprod Dev 83:675-83 |
| Mottier-Pavie, Violaine I; Palacios, Victor; Eliazer, Susan et al. (2016) The Wnt pathway limits BMP signaling outside of the germline stem cell niche in Drosophila ovaries. Dev Biol 417:50-62 |
| Buszczak, Michael; Inaba, Mayu; Yamashita, Yukiko M (2016) Signaling by Cellular Protrusions: Keeping the Conversation Private. Trends Cell Biol 26:526-534 |
| Carreira-Rosario, Arnaldo; Bhargava, Varsha; Hillebrand, Jens et al. (2016) Repression of Pumilio Protein Expression by Rbfox1 Promotes Germ Cell Differentiation. Dev Cell 36:562-71 |
