The activity of adult somatic stem cells has to be precisely controlled and adjusted to the organism's requirements. The underlying regulatory mechanisms are not well understood, but can be studied in the genetically tractable Drosophila intestinal stem cells (ISCs). Preliminary data generated in the laboratories of the two applicants have shown that cell stress and tissue damage can significantly increase the proliferative activity of ISCs. Strikingly, this activation of ISCs requires a concomitant decrease in cellular redox state. Redox based regulation of stem and progenitor cell function has been postulated before, but the genetic and mechanistic basis for this effect remains obscure. The preliminary data on which this proposal is based indicate a key role of the Nrf2 transcription factor, which has previously been mostly associated with antioxidant and detoxification programs. Upon stress exposure of ISCs, Nrf2 function is repressed, permitting the concentration of reactive oxygen species (ROS) to rise, and promoting proliferative competence of these cells. The down regulation of Nrf2 in response to stress and tissues injury is unique to stem cells and contrasts sharply with stress dependent activation of Nrf2 described in most other somatic cell types. The discovery of this unique Nrf2 signaling system that is restricted to stem cells raises interesting questions and offers opportunities for the targeted manipulation of stem cell function. This project will explore the distinctive regulation and the effects of Nrf2 in ISCs. Several lines of experimentation will explore how stress signaling affects Nrf2 to regulate ISC proliferation. Separate experiments will test the hypothesis that Nrf2 and redox control are universal mechanisms regulating stem cell activity, which are not only required to convey the response to direct cell damaging stress, but also to mediate the effects of endocrine differentiation signals. Finally, the mechanisms by which redox changes can alter stem cell function in such profound ways will be explored. For this latter aim experiments will be conducted to identify relevant redox sensing signaling molecules that control stem cell activity. The work described in this proposal will provide a mechanistic understanding of the redox-based mechanisms that control stem cell function and consequently tissue homeostasis. The goal is to test the model that Nrf2 activity determines a reduced, inactive state of ISCs, in which they are protected from oxidative stress, but cannot engage in regenerative processes. Down regulation of Nrf2 function by stress or mitogenic signaling then induces an oxidized state that allows regeneration to proceed. Validation of this model will confirm and mechanistically explain long standing theories on stem and progenitor cell regulation and may suggest strategies and targets for the manipulation of stem cell behavior, for example in cell transplantation paradigms or in the treatment of stem cell diseases.

Public Health Relevance

Somatic stem cells are critical for tissue maintenance and regeneration. Controlling their regenerative capacity and proliferative activity is of fundamental importance for the maintenance of tissue homeostasis. This project investigates redox signaling as a central component of stem cell regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM100196-02
Application #
8420441
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Haynes, Susan R
Project Start
2012-02-06
Project End
2016-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2013
Total Cost
$402,339
Indirect Cost
$141,925
Name
University of Rochester
Department
Genetics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Li, Xuan; Chatterjee, Nirmalya; Spirohn, Kerstin et al. (2016) Cdk12 Is A Gene-Selective RNA Polymerase II Kinase That Regulates a Subset of the Transcriptome, Including Nrf2 Target Genes. Sci Rep 6:21455
Chatterjee, Nirmalya; Tian, Min; Spirohn, Kerstin et al. (2016) Keap1-Independent Regulation of Nrf2 Activity by Protein Acetylation and a BET Bromodomain Protein. PLoS Genet 12:e1006072
Li, Hongjie; Jasper, Heinrich (2016) Gastrointestinal stem cells in health and disease: from flies to humans. Dis Model Mech 9:487-99
Li, Hongjie; Qi, Yanyan; Jasper, Heinrich (2016) Ubx dynamically regulates Dpp signaling by repressing Dad expression during copper cell regeneration in the adult Drosophila midgut. Dev Biol 419:373-381
Pitoniak, Andrew; Bohmann, Dirk (2015) Mechanisms and functions of Nrf2 signaling in Drosophila. Free Radic Biol Med 88:302-13
Adams, Peter D; Jasper, Heinrich; Rudolph, K Lenhard (2015) Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell 16:601-12
Deng, Hansong; Gerencser, Akos A; Jasper, Heinrich (2015) Signal integration by Ca(2+) regulates intestinal stem-cell activity. Nature 528:212-7
Ayyaz, Arshad; Li, Hongjie; Jasper, Heinrich (2015) Haemocytes control stem cell activity in the Drosophila intestine. Nat Cell Biol 17:736-48

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