Objective
Accidental exposure to ionizing radiation frequently results in severe damage to bone marrow and immune functions, resulting in a life-threatening condition, while skin and subcutaneous tissue may receive doses sufficient for severe morbidity and disabilities. Recent advances in molecular and cellular biology provide new avenues for diagnosis and treatment of both bone marrow, immune and skin lesions. Identification and assays for hemopoietic stem cells have become available as well as routine methods to isolate those cells to a high degree of purity. We propose to use this knowledge to develop quantitative assays for diagnosis of residual numbers of stem cells as well as radiation damage to such cells.Simultaneously a large number of cytokines have emerged that control or modulate stem cell proliferation, blood cell production and immune functions. We propose to investigate the use of such growth factors to facilitate the reconstitution of blood cell production and immune functions, either from endogenous stem cells or, in case of high dose exposure, from transplanted subsets of stem cells. This approach will be tested by predictive preclinical studies in rhesus monkeys. In cases of exposure to high doses of radiation, transplantation of (subsets) of stem cells may be life-saving. Alternative sources of donor stem cells have been explored, such as mobilized peripheral blood stem cells and the widely available cord blood cells. It is proposed to characterize the cellular and molecular properties, including growth factor receptor phenotype, of immature stem cells giving rise to rapid reconstitution following transplantation, with special emphasis on peripheral blood stem cells and cord blood cells, and to identify subsets that give rise to accelerated immune reconstitution.This work will then lead to the rapid selection, harvest and quantitative assays for such cells, as well expansion in vitro (prerequisites for developing a stem cell bank). To promote allograft acceptance, the dual approach of antibody facilitated engraftment as well as functional depletion of anti-host T cell reactivity will be pursued. The research proposed will lead to improved early diagnosis of bone marrow damage as well as provide differential treatment regimens for different levels of exposure.
Over-exposure of skin and subcutaneous tissues may be very heterogenous, certain areas being exposed to high doses. Although a number of treatment regimens have been developed to ameliorate the severity of specific aspects of the radiation induced cutaneous syndrome, treatments are only partially effective.
Further progress in this area is dependent on a more profound understanding of the cellular and molecular mechanisms involved. The types of cutaneous reactions seen in accident victims have been developed in the pig by two of the laboratories collaborating in the project. It is proposed to measure the molecular and cellular changes for the different manifestations of the cutaneous syndrome in these models. This will include the determination of radiation-induced alterations of surface antigens, adhesion molecules, endogenous growth factors and their receptors is tissue in relation to dose and time after exposure.
Studies in vivo will be supplemented by in vitro studies with individual cell types and in a model of reconstituted skin. These organotypic cultures could be a powerful tool to study the role of different cell types and cell/cell interactions in this area of radioprotection. Modifications induced in these patterns by known treatment agents such as superoxide dismutase, essential fatty acids and pentoxifylline will be assessed. This will then help to identify their mechanism of action, assist in understanding the underlying mechanisms of radiation damage and lead to the development of new, more effective, methods for the treatment of skin lesions in exposed individuals.
Programme(s)
Call for proposal
Data not availableFunding Scheme
CSC - Cost-sharing contractsCoordinator
3000 DR ROTTERDAM
Netherlands