The long-term goal of this study is to develop new strategies to mitigate and protect radiation-induced hematopoietic injury by delineating the molecular mechanisms responsible for enhancing hematopoietic stem cells (HSC) self-renewal and survival. Radiation therapy commonly results in not only acute hematopoietic suppression but also long-term bone marrow (BM) injury. To date, no effective treatment has been developed to prevent or treat these pathological consequences. Enhancing HSC survival and maintaining their genomic integrity upon radiation are crucial for preservation of HSC self-renewal function and for protection against radiation-induced BM injury. However, the molecular mechanisms for regulating HSC survival and self-renewal are not well defined. HSC number and function demonstrate natural variations, and underlying genetic diversity is an important, yet largely unknown, mechanism involved in the regulation of HSC function. Latexin (Lxn) was previously identified as the first stem cell regulatory gene whose natural variation negatively contributes to the HSC population size in different mouse strains. In preliminary studies, constitutive gene ablation approaches were developed to define the role of Lxn in HSCs and hematopoiesis in normal and radiation stress conditions. Results showed that Lxn inactivation protects HSCs and hematopoietic progenitor cells (HPCs) from radiation- induced cell death, thus mitigating acute hematopoietic suppression and conferring a survival advantage. Moreover, Lxn knockout mice do not develop hematological malignancies following single or fractionated dosages of radiation. Mechanistically, Lxn inactivation in vivo increases HSC self-renewal and survival. At the molecular level, our published and preliminary work showed that ribosomal protein subunit 3 (Rps3) is a novel Lxn-binding protein, and Lxn overexpression inhibits Rps3 activity, thus enhancing radiation sensitivity and toxicity. In addition, the number of human HSCs/HPCs negatively correlates with Lxn expression level, indicating the potential role of Lxn in regulating human hematopoiesis. These findings lead to the hypothesis that Lxn maintains homeostatic HSC and hematopoiesis and inhibition of Lxn function protects against radiation-induced hematopoietic injury via Rps3-dependent prosurvival pathways.
Specific aims are to: 1) determine the cellular mechanisms by which Lxn inactivation enhances HSC survival and self-renewal and confers radioprotection, 2) identify the molecular mechanisms by which Lxn inactivation enhances Lxn-Rps3- NF-kB prosurvival pathway, and 3) determine the role of Lxn in mitigating human hematopoietic cell toxicity from radiation injury. This research will advance understanding of a critical but understudied mechanism involved in the natural regulator of HSC function and self-renewal. By using mouse and human model systems and state-of-the-art molecular and genomic techniques, findings from the proposed study may facilitate to the development of novel mechanism-based therapeutic strategy to protect against radiation-induced BM injury, which could be beneficial for the patients receiving cancer therapy and BM transplantation.

Public Health Relevance

Mitigation and protection of bone marrow cells, particularly hematopoietic (blood forming) stem cells, from radiotherapy-induced acute and permanent injury is critical for the quality of life of cancer patients receiving radiotherapy and bone marrow transplantation. This study will investigate the radiomitigation and radioprotection of inhibition of a novel HSC regulatory gene, latexin, and will have great therapeutic value for patients receiving radiation, chemotherapy and bone marrow transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL124015-03
Application #
9406330
Study Section
Molecular and Cellular Hematology Study Section (MCH)
Program Officer
Bai, Chunyang Brian
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Leins, Hanna; Mulaw, Medhanie; Eiwen, Karina et al. (2018) Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood 132:565-576
Zhang, Cuiping; Liang, Ying (2018) Latexin and hematopoiesis. Curr Opin Hematol 25:266-272
Oben, Karine Z; Alhakeem, Sara S; McKenna, Mary K et al. (2017) Oxidative stress-induced JNK/AP-1 signaling is a major pathway involved in selective apoptosis of myelodysplastic syndrome cells by Withaferin-A. Oncotarget 8:77436-77452
Zhao, Y; Carroll, D W; You, Y et al. (2017) A novel redox regulator, MnTnBuOE-2-PyP5+, enhances normal hematopoietic stem/progenitor cell function. Redox Biol 12:129-138
Liu, Yi; Zhang, Cuiping; Li, Zhenyu et al. (2017) Latexin Inactivation Enhances Survival and Long-Term Engraftment of Hematopoietic Stem Cells and Expands the Entire Hematopoietic System in Mice. Stem Cell Reports 8:991-1004
Oben, Karine Z; Gachuki, Beth W; Alhakeem, Sara S et al. (2017) Radiation Induced Apoptosis of Murine Bone Marrow Cells Is Independent of Early Growth Response 1 (EGR1). PLoS One 12:e0169767
Zhao, Baobing; Tan, Timothy L; Mei, Yang et al. (2016) H2AX deficiency is associated with erythroid dysplasia and compromised haematopoietic stem cell function. Sci Rep 6:19589
Waterstrat, Amanda; Rector, Kyle; Geiger, Hartmut et al. (2016) Quantitative trait gene Slit2 positively regulates murine hematopoietic stem cell numbers. Sci Rep 6:31412
Carroll, Dustin; Howard, Diana; Zhu, Haining et al. (2016) Simultaneous quantitation of oxidized and reduced glutathione via LC-MS/MS: An insight into the redox state of hematopoietic stem cells. Free Radic Biol Med 97:85-94