Around 1% of the US population experience inflammatory diseases of the intestine. Prolonged inflammation and tissue injury has also been proposed to potentiate gastrointestinal (GI) cancer. To understand how cells in the GI tract interact with wide varieties of microbes and pathogenic substances is important for developing therapeutic strategies that alleviate intestinal diseases. This proposal focuses on understanding how Drosophila intestinal stem cells (ISCs) mediate repair after tissue damage. Drosophila midgut has a relatively simple cellular organization, and midgut ISCs have recently been identified that function to replenish the different cell types. Our preliminary results demonstrate that Drosophila ISCs can increase their division rate in response to tissue damage. Using this newly established system, the genetic requirement of insulin receptor is clearly shown to be essential for ISC division. A number of new genes that can regulate ISC growth and division have also been identified via a pilot genetic screen. Because this Drosophila ISC system is relative new and so far very few genes are known to be involved, it is important to first identify more essential genes by genetic approach and establish the framework that regulates ISC division. A well-established genetic framework will help to understand the molecular mechanisms by which ISCs respond to environmental challenges and mediate tissue repair. This proposal includes three specific aims: 1. Test whether insulin signaling is instructive or permissive in ISC division;2. Investigate how Tuberous Sclerosis Complex interacts with the insulin pathway in ISC growth;3. Identify and analyze new components in damage-induced ISC division. The results obtained from studying the genetically amenable Drosophila ISCs should provide important insights into human stem cell- mediated tissue repair, intestinal inflammatory diseases and cancer progression.

Public Health Relevance

We plan to establish Drosophila intestinal stem cell as a novel genetic model system to study gastrointestinal tract interaction with pathogenic stimuli and tissue regeneration. The human gastrointestinal tract is the major nutrient absorption organ that also has immune and endocrine function. It is also a major site for interaction with commensal bacteria and pathogenic substances. The human gastrointestinal tract is a relatively under-explored organ due to the complexity of the organ and the difficulty in experimental manipulation. Drosophila, the common fruit fly, has emerged as a powerful tool for analyzing the function of human disease genes, either as fly homologues or by expressing in transgenic flies the mutated forms of human genes. To study how intestinal stem cells in Drosophila respond to tissue damage and initiate repair will provide important insights into similar processes in humans. The information obtained may yield novel strategies for treatment of inflammatory diseases and cancer.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK083450-05
Application #
8680227
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Carrington, Jill L
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
Li, Qi; Li, Shuangxi; Mana-Capelli, Sebastian et al. (2014) The conserved misshapen-warts-Yorkie pathway acts in enteroblasts to regulate intestinal stem cells in Drosophila. Dev Cell 31:291-304
Yu, Shiyan; Nie, Yingchao; Knowles, Byron et al. (2014) TLR sorting by Rab11 endosomes maintains intestinal epithelial-microbial homeostasis. EMBO J 33:1882-95
Zhou, Bo; Yun, Eun-Young; Ray, Lorraine et al. (2014) Retromer promotes immune quiescence by suppressing Spatzle-Toll pathway in Drosophila. J Cell Physiol 229:512-20
Amcheslavsky, Alla; Song, Wei; Li, Qi et al. (2014) Enteroendocrine cells support intestinal stem-cell-mediated homeostasis in Drosophila. Cell Rep 9:32-9
Nirala, Niraj K; Rahman, Motiur; Walls, Stanley M et al. (2013) Survival response to increased ceramide involves metabolic adaptation through novel regulators of glycolysis and lipolysis. PLoS Genet 9:e1003556
Cheng, Wei; Ip, Y Tony; Xu, Zuoshang (2013) Gudu, an Armadillo repeat-containing protein, is required for spermatogenesis in Drosophila. Gene 531:294-300
Ren, Fangfang; Shi, Qing; Chen, Yongbin et al. (2013) Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration. Cell Res 23:1133-46
Amcheslavsky, Alla; Ip, Y Tony (2012) Be a good neighbor: organ-to-organ communication during the innate immune response. Cell Host Microbe 11:323-4
Amcheslavsky, Alla; Ito, Naoto; Jiang, Jin et al. (2011) Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells. J Cell Biol 193:695-710
Kaneko, Satoshi; Chen, Xiaochu; Lu, Peiyuan et al. (2011) Smad inhibition by the Ste20 kinase Misshapen. Proc Natl Acad Sci U S A 108:11127-32

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