Currently there are no available agents to offer to victims after radiation exposure to mitigate acute gastrointestinal syndrome (AGS). FGF-P is a powerful radiation mitigator, which relieves AGS when given after irradiation. FGF-P rescues mice in LD50/7 experiments, increases survival duration, improves crypt proliferation and number, it reduces diarrhea, bleeding, endotoxin level, and improves endocrine and exocrine function. This dimerized peptide is 17 amino acids and features an FGF receptor binding domain and a linking element. The advantages of FGF-P over native FGF-2 are: 1) it is stable under severe conditions; 2) it can be self-administrated i.m. and 3) it can be synthesized in a large quantity with high purity. Mechanistically, we have shown many benefits of FGF-P in acute GI syndrome: 1) greater preservation and increased proliferation of crypt stem cells; 2) mouse strain independent response; 3) improved recovery of bone marrow cellularity; and 4) reduced endotoximia. No deaths were seen at doses 200-fold higher than the effective dose. Based on this promising data, we hypothesize that FGF-P can be developed as a novel mitigation agent to be given after radiation exposure for acute gastrointestinal syndrome. ? ? For this, we will focus on the following aims: ? ? 1) To measure the pharmacokinetics of FGF-P (month 1-9): 3H labeled FGF-P will be injected into normal and irradiated mice. Drug uptake in the blood, bowel, and other organs will be measured in control animals and animals pre-exposed to radiation. ? ? 2) To define the optimal dose and schedule of FGF-P (month 6-18): We will test different dose, schedule and the allowable delay to the first dose in three strains of mice. A DMF >1.2 (dose modification factor) or a prolongation of survival time >50% is the minimal goal. Survival (LD50/7), GI function (stool hemoccult; gross evaluation of stool formation; plasma secretin, amylase, glucose, and insulin) as well as systemic surrogate marker (levels of endotoxin and inflammatory molecules) will be measured. ? ? 3) To measure the interspecies binding and activation of FGF receptors (month 1-15). These measurements will make it possible to determine the optimal dose for scaling to humans. ? ? The results of these pre-clinical studies will provide the basis for eventual approval through the animal rule. A preliminary drug development plan has already been discussed with the FDA. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
NIH Challenge Grants and Partnerships Program (RC1)
Project #
1RC1AI078519-01
Application #
7472928
Study Section
Special Emphasis Panel (ZAI1-MP-I (S3))
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2007-09-15
Project End
2010-02-28
Budget Start
2007-09-15
Budget End
2010-02-28
Support Year
1
Fiscal Year
2007
Total Cost
$1,000,000
Indirect Cost
Name
University of Rochester
Department
Radiation-Diagnostic/Oncology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Chen, Chun; Yang, Shanmin; Zhang, Mei et al. (2016) Triptolide mitigates radiation-induced pulmonary fibrosis via inhibition of axis of alveolar macrophages-NOXes-ROS-myofibroblasts. Cancer Biol Ther 17:381-9
Yang, Shanmin; Zhang, Mei; Chen, Chun et al. (2015) Triptolide Mitigates Radiation-Induced Pulmonary Fibrosis. Radiat Res 184:509-17
Casey-Sawicki, Kate; Zhang, Mei; Kim, Sunghee et al. (2014) A basic fibroblast growth factor analog for protection and mitigation against acute radiation syndromes. Health Phys 106:704-12
Yin, Liangjie; Vijaygopal, Pooja; Menon, Rejeesh et al. (2014) An amino acid mixture mitigates radiation-induced gastrointestinal toxicity. Health Phys 106:734-44
Chen, Chun; Yang, Shanmin; Zhang, Mei et al. (2013) In vitro Sirius Red collagen assay measures the pattern shift from soluble to deposited collagen. Adv Exp Med Biol 765:47-53
Ma, Jun; Hou, Yanqian; Han, Deping et al. (2013) Fibroblast growth factor-peptide promotes bone marrow recovery after irradiation. Adv Exp Med Biol 765:155-161
Zhang, Mei; Zhang, Bingrong; Guo, Yansong et al. (2013) Alteration of circulating mitochondrial DNA concentration after irradiation. Adv Exp Med Biol 765:371-377
Ma, Jun; Han, Deping; Zhang, Mei et al. (2013) Alteration of plasma galactose/N-acetylgalactosamine level after irradiation. Adv Exp Med Biol 765:147-153
Han, Deping; Zhang, Mei; Ma, Jun et al. (2012) Transition pattern and mechanism of B-lymphocyte precursors in regenerated mouse bone marrow after subtotal body irradiation. PLoS One 7:e46560
Zhang, Kunzhong; Tian, Yeping; Yin, Liangjie et al. (2011) Fibroblast growth factor-peptide improves barrier function and proliferation in human keratinocytes after radiation. Int J Radiat Oncol Biol Phys 81:248-54

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