Bioactive Peptides for Mitigation of AGS and Acute Radiation Injury

Summary

Principal Investigator: Lurong Zhang
Abstract: DESCRIPTION (provided by applicant): Ionizing radiation (IR) released by detonation can cause the most overwhelming disaster. In acute radiation injury (ARI), the major causes of death are the acute gastrointestinal syndrome (AGS) and BMS (bone marrow syndrome). Pathophysiologically, GI and BM closely associate with each other and the treatment should be comprehensive for both. Neglecting BM during the GI treatment will result in failure of both GI and BM. Giving growth factors (GFs) is more practical than transfusion of blood or BM in a mass casualty scenario. Compared to the native GFs, the well-designed peptides with GF binding domain could possess similar activity with attractive properties of peptides being more stable, no antigenicity, low toxicity and inexpensive. Studies alone this line, we have designed and synthesized several bioactive peptides, such as FGF-P (binding domain of fibroblast growth factor 2), TPO-P (binding domain shared by thrombopoietin and erythropoietin) and NPY (Neuropeptide Y) and demonstrated that these bioactive peptides exerted certain mitigation effect on mice with lethal IR damage of both GI an BM even give at 4-24 hr post-IR. However, the use of a single peptide could not rescue 100% of IR mice. Obviously, the IR damage is systemic and involved in multi-organs and treatment should be comprehensive. To improve the efficacy of mitigation, we will treat GI and BM damages at the same time via utilizing FGF-P, TPO-P, G-CSF-P and NPY. First, the assays with state-of-art Biacore 2000 instrument, phosphorylation of signal transduction molecules and proliferation of GI and BM cells will be carried out to select the peptides with high bioactivity. Then, the ones with high bioactivities will be used in combinations or in sequence for their mitigation effect given >24 hours post-IR in mice received lethal dose IR for both GI and BM damages. Finally, the ones that achieve a 1.2 DMF (dose modification factor) or a 50% prolongation of survival time in either GI or BM model will be studied for the action mechanism by examining the electrolyte transport for improved function of GI mucosa or the blood differential counts for enhanced BM regeneration. If successful, the bioactive peptides and the optimal dose and schedule would provide powerful mitigation for victims of both IR disaster and cancer treatment toxicity, which will not only reduce the casualty in the special event and the side effect of chemotherapy, but also reduce the overwhelming economic burden on health care system due to use the cheap and stable small peptides rather than expensive native proteins. Public Health Relevance: Exposure to ionizing radiation (IR) causes severe multi-organ damages, especially the AGS (acute gastrointestinal syndrome) and BMS (bone marrow syndrome) in ARI (Acute Radiation Injury). Searching for the effective regiments that can be easily applied in a mass casualty scenario remains a high priority. So far, besides the transfusion of blood and BM cells, the growth factors (GFs) are the key regiments for AGS and ARI. Based on the facts that: 1) body's most powerful regulators, such as endocrine molecules and GFs, are polypeptides;and 2) the binding domain of GFs could exert similar function as native protein with properties of peptide being more stable, no antigenicity, low toxicity and inexpensive, we have demonstrated that our bioactive peptides, such as FGF-P (binding domain of fibroblast growth factor 2), TPO-P (binding domain shared by thrombopoietin and erythropoietin) and NPY (Neuropeptide Y) exerted certain mitigation effect on AGS and ARI. However, with a single peptide, it could not reach 100% rescuing effect. To improve this, we will: 1) select high binding affinity FGF-P, TPO-P, G-CSF-P and NPY with Biacore assay, phosphorylation of signal transduction molecules and proliferation assay;2) test the mitigation effect of 4 bioactive peptides in combination or in sequential use starting at >24 hours post lethal dose IR in GI or BM mouse models;and 3) define their action mechanisms by measuring the alterations of electrolyte transport as functions of GI mucosa or by monitoring the blood differential counts as an index for BM regeneration. If successful, the developed growth stimulating peptides and its optimal use strategy will not only fill the gap in current medical countermeasures against AGS and ARI, but also be of benefit to millions of cancer patients each year who undergo chemotherapy or radiotherapy which damages the GI and BM systems. It would also reduce the overwhelming economic burden on health care system due to use the cheap and stable bioactive peptides rather than the expensive native proteins of growth factors.
Funding Period: ----------------2010 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi In vitro Sirius Red collagen assay measures the pattern shift from soluble to deposited collagen
    Chun Chen
    Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA
    Adv Exp Med Biol 765:47-53. 2013
  2. ncbi Alteration of plasma galactose/N-acetylgalactosamine level after irradiation
    Jun Ma
    Institute of Digestive Diseases, Zhengzhou University, Henan, China
    Adv Exp Med Biol 765:147-53. 2013
  3. ncbi Fibroblast growth factor-peptide promotes bone marrow recovery after irradiation
    Jun Ma
    Institute of Digestive Diseases, Zhengzhou University, Henan, China
    Adv Exp Med Biol 765:155-61. 2013
  4. ncbi Alteration of circulating mitochondrial DNA concentration after irradiation
    Mei Zhang
    Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA
    Adv Exp Med Biol 765:371-7. 2013
  5. pmc Transition pattern and mechanism of B-lymphocyte precursors in regenerated mouse bone marrow after subtotal body irradiation
    Deping Han
    First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
    PLoS ONE 7:e46560. 2012

Detail Information

Publications5

  1. ncbi In vitro Sirius Red collagen assay measures the pattern shift from soluble to deposited collagen
    Chun Chen
    Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA
    Adv Exp Med Biol 765:47-53. 2013
    ....
  2. ncbi Alteration of plasma galactose/N-acetylgalactosamine level after irradiation
    Jun Ma
    Institute of Digestive Diseases, Zhengzhou University, Henan, China
    Adv Exp Med Biol 765:147-53. 2013
    ..These IR-induced alterations might relate to the release of glycoproteins into the blood and the damage of the proteins and genes that are related to the glycosylation process...
  3. ncbi Fibroblast growth factor-peptide promotes bone marrow recovery after irradiation
    Jun Ma
    Institute of Digestive Diseases, Zhengzhou University, Henan, China
    Adv Exp Med Biol 765:155-61. 2013
    ..The increase of LT-HSC in bone marrow leads to a concomitant increase of pro-B and pre-B cells followed by leukocytes and granulocytes, which in turn enhance immunity against infection...
  4. ncbi Alteration of circulating mitochondrial DNA concentration after irradiation
    Mei Zhang
    Department of Radiation Oncology, University of Florida, Gainesville, FL 32610, USA
    Adv Exp Med Biol 765:371-7. 2013
    ..The alteration of mtDNA was not dose-dependent or time-dependent; hence, it is unlikely to be an effective biodosimeter...
  5. pmc Transition pattern and mechanism of B-lymphocyte precursors in regenerated mouse bone marrow after subtotal body irradiation
    Deping Han
    First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China
    PLoS ONE 7:e46560. 2012
    ....