Tissue self renewal is essential to the viability of the adult organism. In the intestine, the renewal process has built-in flexibility to adapt to external influences by altering the proliferation/death equilibrium. However, the signals that trigger adaptation and the mechanisms that re-equilibrate homeostatic balance are virtually unexplored. With the recent discovery that multipotent stem cells renew the intestinal lining in the adult Drosophila midgut, the powerful advantages of the Drosophila system-superior genetic tools, sophisticated cellular analysis, and high experimental tractability-can be applied to the outstanding problem of how tissue homeostasis is dynamically regulated. The ultimate goals of this research are to understand how death and proliferation are coordinated within tissues to achieve homeostasis and to uncover the mechanisms that enable homeostatic flexibility. This proposal focuses on nutrient-driven mucosal remodeling, a paradigm of intestinal adaptation. Combined genetic and cellular approaches will be used to examine the hypothesis that distinct systemic and local mechanisms regulate nutrient-driven adaptation.
Aim 1 will characterize how nutrients alter the spatial and temporal profile of the proliferaton [sic]/death balance in intestinal homeostasis.
Aim 2 will investigate the role of systemic, nutrient-sensitive endocrine signals, particularly insulin and a Drosophila neuropeptide Y homolog, in homeostatic remodeling.
Aim 3 will investigate the role of local cellular interactions by determining how enterocytes act through tissue structure to control the proliferation of nearby stem cells, culminating in a genetic screen to identify novel genes, both nutrient-sensitive and -insensitive, that promote short-range homeostatic control. The results from these studies will shed new light on the pathways that underlie intestinal adaptation. Under the mentorship of Dr. David Bilder and co-mentorship of Dr. John Forte, both leaders in the irrespective fields, the candidate will gain expertise in newer areas of GI physiology, stem cell biology, and genetic screening while pursuing her long-standing interest in epithelial tissue dynamics. This research and training plan will faciliate [sic] the candidate's progression to autonomy by helping her establish an independent and complementary research project within the UC Berkeley Department of Molecular and Cell Biology.
The ability of the intestine to renew itself can be overwhelmed by injury and disease, leading to impaired nutrient absorption and long-term intravenous feeding. To develop better therapies, we need to know more about the basic genes and processes that control intestinal renewal. Studying intestinal renewal in fruit flies, a simple animal model, will generate new leads that can be explored further in mammals.
|O'Brien, Lucy Erin; Bilder, David (2013) Beyond the niche: tissue-level coordination of stem cell dynamics. Annu Rev Cell Dev Biol 29:107-36|
|O'Brien, Lucy Erin (2013) Regional specificity in the Drosophila midgut: setting boundaries with stem cells. Cell Stem Cell 13:375-6|
|O'Brien, Lucy Erin; Soliman, Sarah S; Li, Xinghua et al. (2011) Altered modes of stem cell division drive adaptive intestinal growth. Cell 147:603-14|