The hematopoietic system is exquisitely sensitive to radiation injury, however, little is known of the specific radiosensitivity of hematopoietic progenitor and precursors intermediates in the complex milieu of the marrow. This proposal is focused on understanding, and thus better mitigating, the effects of radiation on the erythroid and megakaryocyte lineages that originate from a common bipotential progenitor, share several cytokine growth factors, but have distinct cellular niches and unique processes of precursor maturation. We hypothesize that their biological differences lead to differential radiation sensitivity and their shared features provide opportunities for common mitigation.
In Aim 1, we will determine the differential radiosensitivity of erythroid and megakaryocyte progenitors and precursors. Several cytokines are known to protect both erythroid and megakaryocyte precursors from cell death.
In Aim 2, we will define the ability of single and combination cytokine therapy to mitigate radiation injury and explore whether the emergence of these two lineages from a common progenitor causes cytokine therapy to favor the mitigation of one lineage to the detriment of the other.
In Aim 3, we will investigate radiation damage to the distinct niches of erythroid and megakaryocyte precursors, and thus lay the groundwork for future novel approaches of mitigating hematopoietic precursors by protecting their cellular niches. A bioterrorist attack or major nuclear disaster would lead not only to acute external radiation exposure, but may also involve secondary internal exposure through inhalation and ingestion of radioactive particulates, as has been seen in a number of nuclear incidents.
In Aim 4, we will take advantage of a murine model of internal exposure recently established at the University of Rochester to begin to delineate the effects of chronic, low dose, internal radiation on the bone marrow. A better understanding of the response of the hematopoietic system and its microenvironment to radiation exposure will provide for a rational approach to its mitigation in the face of a nuclear accident or attack and, thus, enhance hematopoietic recovery and improve survival of primary victims as well their rescuers. PUBLIC HEALTH STATEMENT: The proposed research is designed to learn which blood cells in the bone marrow are sensitive to radiation and to learn how to protect these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080401-05
Application #
8293353
Study Section
Special Emphasis Panel (ZAI1-TP-I (M1))
Program Officer
Dicarlo-Cohen, Andrea L
Project Start
2008-07-22
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$377,339
Indirect Cost
$132,314
Name
University of Rochester
Department
Pediatrics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Hyrien, O; Peslak, S A; Yanev, N M et al. (2015) Stochastic modeling of stress erythropoiesis using a two-type age-dependent branching process with immigration. J Math Biol 70:1485-521
Niswander, Lisa M; Fegan, Katherine H; Kingsley, Paul D et al. (2014) SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood 124:277-86
Niswander, Lisa M; McGrath, Kathleen E; Kennedy, John C et al. (2014) Improved quantitative analysis of primary bone marrow megakaryocytes utilizing imaging flow cytometry. Cytometry A 85:302-12
Peslak, Scott A; Wenger, Jesse; Bemis, Jeffrey C et al. (2011) Sublethal radiation injury uncovers a functional transition during erythroid maturation. Exp Hematol 39:434-45
McGrath, Kathleen E; Bushnell, Timothy P; Palis, James (2008) Multispectral imaging of hematopoietic cells: where flow meets morphology. J Immunol Methods 336:91-7