Hematopoietic failure is the major cause of death in Acute Radiation Sickness. Unfortunately, few therapies exist that are effective at mitigating radiation-induced damage to the hematopoietic system. We hypothesized that cells within the bone marrow microenvironment, specifically endothelial cells (ECs), regulate hematopoietic regeneration following radiation injury. Our recent studies validated this hypothesis, demonstrating that human ECs produce soluble proteins that induce the expansion of human hematopoietic stem cells (HSCs) in vitro and transplantation of ECs alone rescued animals from lethal radiation exposure and accelerated hematopoietic reconstitution in vivo. A genetic screen revealed pleiotrophin (PTN), a heparin binding growth factor with no known function in hematopoiesis, as 25-fold overexpressed in ECs with HSC-supportive activity. Our preliminary studies demonstrate that treatment with PTN induces a 10-fold expansion of murine HSCs in culture and systemic administration of PTN to irradiated mice demonstrates that PTN treatment markedly accelerates reconstitution of BM HSCs and progenitor cells compared GCSF- or saline-treated controls. We hypothesize that PTN regulates the selfrenewal and regeneration of BM HSCs in vitro and in vivo and that PTN is an excellent candidate mitigator of radiation-induced hematopoietic failure. In order to test our hypothesis, we propose the following Specific Aims: 1) Determine the function of PTN in regulating HSC self renewal and homeostasis. 2) Determine if PTN can mitigate radiation-induced myelosuppression in vivo, and 3) Test the efficacy of PTN in mitigating human hematopoietic cell toxicity from radiation injury. Our broad objective in this proposal is to deliver a translatable and potent mitigator of radiation-induced hematopoietic injury. Our preliminary results demonstrate that PTN is a soluble growth factor for murine and human HSCs and systemic administration of PTN for 1 week induces the accelerated regeneration of BM HSCs and progenitor cells in vivo compared to GCSF-treated mice. PTN has therapeutic potential as a mitigator of the radiation-induced hematopoietic syndrome.

Public Health Relevance

In a radiation mass casualty event, the majority of deaths from radiation sickness will be caused by bone marrow failure. Unfortunately, few treatments exist to ameliorate radiation-induced toxicity to the bone marrow. We have discovered a novel protein which stimulates the self renewal of bone marrow stem cells in vitro and the regeneration of the blood system in vivo after radiation injury. This protein is a candidate therapeutic for the treatment of victims of acute radiation sickness.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-KS-I)
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Duke University
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Linz, Brandon M L; Neely, Crystal J; Kartchner, Laurel B et al. (2017) Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis. J Immunol 198:2426-2433
Racioppi, Luigi; Lento, William; Huang, Wei et al. (2017) Calcium/calmodulin-dependent kinase kinase 2 regulates hematopoietic stem and progenitor cell regeneration. Cell Death Dis 8:e3076
Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626
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
Himburg, Heather A; Doan, Phuong L; Quarmyne, Mamle et al. (2017) Dickkopf-1 promotes hematopoietic regeneration via direct and niche-mediated mechanisms. Nat Med 23:91-99
Jha, Sushmita; Brickey, W June; Ting, Jenny Pan-Yun (2017) Inflammasomes in Myeloid Cells: Warriors Within. Microbiol Spectr 5:
DeBo, Ryne J; Lees, Cynthia J; Dugan, Greg O et al. (2016) Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques. Radiat Res 186:55-64
Mont, Stacey; Davies, Sean S; Roberts Second, L Jackson et al. (2016) Accumulation of isolevuglandin-modified protein in normal and fibrotic lung. Sci Rep 6:24919

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