Abstract

The overall objectives of this project are to explore how nucleic acids released from dead and dying cells following irradiation induce inflammation and coagulation factor consumption and to determine if nucleic acid scavengers can mitigate such effects and prolong survival.
The specific aims are: 1) To explore how extracellular DNA/RNA and nucleic acid-containing complexes released from dead and dying cells following irradiation activate innate immune responses and induce inflammation and/or activate the contact pathway of coagulation and result in coagulation factor consumption. 2) To determine if nucleic acid scavengers can bind and counteract proinflammatory and procoagulant effects of irradiation associated nucleic acids and nucleic acid-containing complexes in cell culture and coagulation assays. 3) To determine if nucleic acid scavengers can improve survival of animals following lethal irradiation and reduce inflammatory shock and coagulation factor consumption and associated bleeding following irradiation without compromising the ability of the animals to respond to infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI067798-12
Application #
9128544
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

Cline, John Mark; Dugan, Greg; Bourland, John Daniel et al. (2018) Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation. Antioxidants (Basel) 7:
Farris, Michael; McTyre, Emory R; Okoukoni, Catherine et al. (2018) Cortical Thinning and Structural Bone Changes in Non-Human Primates after Single-Fraction Whole-Chest Irradiation. Radiat Res 190:63-71
Naqvi, Ibtehaj; Gunaratne, Ruwan; McDade, Jessica E et al. (2018) Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis. Mol Ther 26:1020-1031
Ghandhi, Shanaz A; Turner, Helen C; Shuryak, Igor et al. (2018) Whole thorax irradiation of non-human primates induces persistent nuclear damage and gene expression changes in peripheral blood cells. PLoS One 13:e0191402
Castle, Katherine D; Daniel, Andrea R; Moding, Everett J et al. (2018) Mice Lacking RIP3 Kinase are not Protected from Acute Radiation Syndrome. Radiat Res 189:627-633
Jha, Sushmita; Brickey, W June; Ting, Jenny Pan-Yun (2017) Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectr 5:
Lee, Jaewoo; Jackman, Jennifer G; Kwun, Jean et al. (2017) Nucleic acid scavenging microfiber mesh inhibits trauma-induced inflammation and thrombosis. Biomaterials 120:94-102
Andrews, Rachel N; Metheny-Barlow, Linda J; Peiffer, Ann M et al. (2017) Cerebrovascular Remodeling and Neuroinflammation is a Late Effect of Radiation-Induced Brain Injury in Non-Human Primates. Radiat Res 187:599-611
Chen, Liang; Wilson, Justin E; Koenigsknecht, Mark J et al. (2017) NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat Immunol 18:541-551
Fanning, K M; Pfisterer, B; Davis, A T et al. (2017) Changes in microvascular density differentiate metabolic health outcomes in monkeys with prior radiation exposure and subsequent skeletal muscle ECM remodeling. Am J Physiol Regul Integr Comp Physiol 313:R290-R297

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