Normal tissue toxicity to the gastrointestinal (Gl) tract occurs frequently with chemoradiotherapy and represents a major clinical challenge. Unfortunately, no effective treatments exist to combat this significant clinical problem. The luminal epithelia of the Gl tract exist in physiologic hypoxia, and thus hypoxic signaling is crucial to the their survival and normal functions. Hypoxia-inducible factor-1 (HlF-1) is a transcription factor at the heart of the cellular hypoxia response whose levels fluctuate inversely with cellular oxygen tension. Stabilized HIF-1 expression has been shown to be critical for normal intestinal homeostasis as well as survival during inflammatory challenges. HIF-1 is required to maintain several basic functions of the intestine, such as barrier and absorptive functions. Augmenting HIF-1 expression in the intestine improves epithelial barrier functions, increases nutrient absorption and reduces apoptosis in response to infection and inflammatory stress. Conversely, intestinal specific knockouts of HIF-1 cause increased epithelial apoptosis in murine models of colitis. The oxygen dependent regulation of HIF is chiefly mediated through the prolyl hydroxylase domain (PHD)-containing proteins which hydroxylate proline moieties on HIF, and serve as a recognition site for the von Hippel Lindau (VHL) protein, which targets HIF for proteasomal destruction. To date, three oxygen-dependent prolyl hydroxylases have been identified (PHD1-3), however, the roles of each isoform in intestinal homeostasis is not clear. Because PHD proteins regulate HIF levels, and HIF, in turn protects the gut from inflammatory stress, it is our hypothesis that the PHD proteins regulates radiosensitivity in the gastrointestinal tract, such that deletion of specific PHD isoforms will afford radioprotection of the gut through HIF-medlated effects on epithelial integrity and crypt regeneration. In this proposal, we will: 1) investigate the specific contributions of PHD 1-3 on radioprotecting the Gl tract from hypofractionated and fractionated radiation with Project 2 and Core B, 2) determine the mechanisms of radioprotection by PHD inhibition with Project 3;3) explore the role of PHD 1-3 in the radiation response ofthe intestinal stem cell with Project 2, 4) determine the efficacy of a small molecule PHD inhibitor to protect the Gl tract with Project 2;and 5) determine the therapeutic efficacy of PHD 1-3 knockouts and small molecule inhibitors of PHD activity on tumor growth in response to radiation relative to normal tissue radioprotection with Project 4. This project represents a new paradigm change in the development of radioprotectors in that we are investigating the physiological basis of tissue radioprotection through alterations in epithelial barrier function.
Gastrointestinal (Gl) toxicity is one of the most common and distressing acute side effects of systemic chemotherapy or abdominopelvic radiation therapy. For instance, nearly 75% of patients receiving pelvic radiotherapy experience acute radiation proctopathy, which often involves diarrhea and cramping. The sensitivity of the normal cells in the Gl tract limits dose escalation of radiotherapy to tumors in the abdomen or pelvis, and thereby hinder tumor eradication. Therefore, the need exists for a Gl tract radioprotector.
|Vilalta, Marta; Brune, Jourdan; Rafat, Marjan et al. (2018) The role of granulocyte macrophage colony stimulating factor (GM-CSF) in radiation-induced tumor cell migration. Clin Exp Metastasis 35:247-254|
|Tandon, Neha; Thakkar, Kaushik N; LaGory, Edward L et al. (2018) Generation of Stable Expression Mammalian Cell Lines Using Lentivirus. Bio Protoc 8:|
|Yang, Zhifen; Zhang, Jing; Jiang, Dadi et al. (2018) A Human Genome-Wide RNAi Screen Reveals Diverse Modulators that Mediate IRE1?-XBP1 Activation. Mol Cancer Res 16:745-753|
|Benej, Martin; Hong, Xiangqian; Vibhute, Sandip et al. (2018) Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A 115:10756-10761|
|Rafat, Marjan; Aguilera, Todd A; Vilalta, Marta et al. (2018) Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients. Cancer Res 78:4241-4252|
|Saiki, Julie P; Cao, Hongbin; Van Wassenhove, Lauren D et al. (2018) Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proc Natl Acad Sci U S A 115:6279-6284|
|Olcina, Monica M; Kim, Ryan K; Melemenidis, Stavros et al. (2018) The tumour microenvironment links complement system dysregulation and hypoxic signalling?. Br J Radiol :20180069|
|Castellini, Laura; Moon, Eui Jung; Razorenova, Olga V et al. (2017) KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. Nucleic Acids Res 45:3674-3692|
|VandeKopple, Matthew J; Wu, Jinghai; Baer, Lisa A et al. (2017) Stress-responsive HILPDA is necessary for thermoregulation during fasting. J Endocrinol 235:27-38|
|Peinado, Héctor; Zhang, Haiying; Matei, Irina R et al. (2017) Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer 17:302-317|
Showing the most recent 10 out of 203 publications