The targeted aim of Project 4 is to develop therapies to mitigate late effects of radiation on the hematopoietic system. This robust cellular system is damaged by radiation resulting in life-threatening infections, anemia, and bleeding. While the """"""""hematopoietic syndrome"""""""" is well characterized, much less is known about the longterm effects of sublethal radiation on the bone marrow. Our preliminary studies indicate that external sublethal radiation leads to late cytopenias and striking decreases in hematopoietic stem cells (HSC) numbers and function. These preliminary findings support the hypothesis that sublethal external radiation causes significant late marrow injury particularly to the HSC compartment. A bioterrorist attack or nuclear disaster would lead not only to acute external radiation exposure, but also to internal exposure through inhalation and/or ingestion of radioactive particulates. In collaboration with current U19 investigators, we have determined that low dose internal 137Cs, unlike external radiation, causes unexpectedly severe late effects to hematopoietic progenitors. We hypothesize that internal radiation may cause a distinct, previously unexplored pattern of hematopoietic injury. We also hypothesize that combined external plus internal radiation may cause synergistic hematopoietic damage and lead to marrow failure.
In Aims 1 and 2, we will more fully define the late effects of external versus internal versus combined external/internal sublethal irradiation on the stem, progenitor, and peripheral blood cell compartments. A better understanding of the response of the hematopoietic system to irradiation will provide for a rational approach to its mitigation following nuclear accident or attack. The substance P analog, Homspera, has been shown to increase hematopoietic progenitor numbers and protect mice from lethal radiation.
In Aim 3, we will test the ability of Homspera, as well as the antioxidant EUK-207, to mitigate the late effects of radiation-induced injury to the hematopoietic system. During ontogeny, the sites of hematopoiesis transition from yolk sac to fetal liver to postnatal bone marrow.
In Aim 4, we will test the hypothesis that the hematopoietic system is highly vulnerable to radiation injury as it migrates from liver to marrow in the early post-natal period.

Public Health Relevance

Our goals are to better understand the effects of radiation on the blood-forming system and to use this knowledge to test medications to see if they can protect the body from radiation damage. We will also look at the effect of radiation on very young mice to see if they are particularly susceptible to injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI091036-03
Application #
8381732
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$378,248
Indirect Cost
$114,447
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
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Monin, L; Griffiths, K L; Slight, S et al. (2015) Immune requirements for protective Th17 recall responses to Mycobacterium tuberculosis challenge. Mucosal Immunol 8:1099-109
Monin, Leticia; Griffiths, Kristin L; Lam, Wing Y et al. (2015) Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis. J Clin Invest 125:4699-713
Groves, Angela M; Johnston, Carl J; Misra, Ravi S et al. (2015) Whole-Lung Irradiation Results in Pulmonary Macrophage Alterations that are Subpopulation and Strain Specific. Radiat Res 184:639-49
Evans, Andrew G; Calvi, Laura M (2015) Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis. Ann N Y Acad Sci 1335:63-77

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