Adult tissue stem cells are believed to be responsible for maintaining tissue homeostasis and regeneration following injury in most tissues. The small intestine is one of the most sensitive organs to radiation-induced damage, which is the major complication in abdominal and pelvic radiotherapy with no effective treatment. The intestinal stem cells (ISCs) are located at or near the bottom of crypts in a unique yet poorly defined microenvironment (""""""""niche"""""""") composed of several cell types derived from the bone marrow (BM). However, their identity remained elusive until recently. Genetic evidence demonstrated that the crypt-based columnar cells (CBCs) interspersed among Paneth cells marked by Lgr5 and some +4 cells immediately above Paneth cells marked by Bmi-1, represent perhaps distinct subsets of ISCs. Therefore, how their functions are regulated by intrinsic and extrinsic (niche-related) programs to participate in intestinal regeneration following injury is poorly understood. Work from us and others indicate that the BH3-only protein PUMA and cyclin-dependent kinase inhibitor p21 regulate the survival and regeneration of intestinal and hematopoietic systems, and the bone marrow modulates intestinal radiosensitivity. We hypothesize that both apoptosis and cell cycle arrest critically regulate the survival and regeneration of intestinal stem cells following radiation through intrinsic and extrinsic mechanisms. In this proposal, we will combine a novel ISC lineage marking and tracing mouse model with various knockout and transplantation models to 1) define the role of ISCs in crypt regeneration following radiation and develop assays for their isolation and characterization;2) demonstrate a potential coordination of PUMA and p21 in modulating the survival and regeneration of ISCs;and 3) define the potential bone marrow contributions to intestinal regeneration. We believe that our studies can lead to a better understanding of ISC biology, and new models and strategies for isolation, characterization and manipulation of these critical cells for therapeutic purposes.

Public Health Relevance

The proposed studies aim to determine the underlying molecular mechanisms governing the injury, survival and regeneration of intestinal stem cells following radiation, and to develop assays for their isolation and characterization. Such studies can help devise strategies to combat intestinal damage caused by radiotherapy or accidental radiation exposure.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1-GRB-8 (O1))
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Carrington, Jill L
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University of Pittsburgh
Schools of Medicine
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Chen, Dongshi; Tong, Jingshan; Yang, Liheng et al. (2018) PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc Natl Acad Sci U S A 115:3930-3935
Knickelbein, Kyle; Tong, Jingshan; Chen, Dongshi et al. (2018) Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene 37:4599-4610
Fletcher, Rochelle; Wang, Yi-Jun; Schoen, Robert E et al. (2018) Colorectal cancer prevention: Immune modulation taking the stage. Biochim Biophys Acta Rev Cancer 1869:138-148
Tong, Jingshan; Tan, Shuai; Nikolovska-Coleska, Zaneta et al. (2017) FBW7-Dependent Mcl-1 Degradation Mediates the Anticancer Effect of Hsp90 Inhibitors. Mol Cancer Ther 16:1979-1988
Tong, Jingshan; Wang, Peng; Tan, Shuai et al. (2017) Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells. Cancer Res 77:2512-2521
Tong, J; Tan, S; Zou, F et al. (2017) FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene 36:787-796
Wei, Liang; Leibowitz, Brian J; Wang, Xinwei et al. (2016) Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. J Clin Invest 126:4076-4087
Chen, Dongshi; Yu, Jian; Zhang, Lin (2016) Necroptosis: an alternative cell death program defending against cancer. Biochim Biophys Acta 1865:228-36
Wang, Yang; Wang, Xinwei; Flores, Elsa R et al. (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646-60
Chen, Xiaojun; Song, Xiaomeng; Yue, Wen et al. (2015) Fibulin-5 inhibits Wnt/?-catenin signaling in lung cancer. Oncotarget 6:15022-34

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