Hyaluronan facilitates hematopoietic recovery following ionizing irradiation

描述（由申请人提供）：电离辐射对人体许多器官和组织有害，包括造血系统。除了消除增殖的造血祖细胞外，照射还会影响造血支持生态位的结构和功能。缺乏能够使电离照射后造血生态位功能正常化的药物，反映了我们在基础干细胞生物学方面的知识差距，并且仍然是最佳治疗方法的障碍。我们之前已经证明透明质酸（HA）有助于骨髓中造血生态位的结构，并支持所有造血谱系的产生。然而，在辐照过程中，透明质酸发生化学降解，导致生态位内造血稳态失衡。该项目将解决外源性HA是否可用于促进不同剂量照射后造血功能恢复的问题。在Specific Aim 1中，我们将通过监测外周血中成熟造血细胞和骨髓中造血干细胞和承诺祖细胞的数量，来测试透明质酸对致死照射和骨髓移植小鼠造血功能恢复的影响。由于透明质酸的生物效应是由其大小决定的，我们将通过测试一组确定大小的透明质酸聚合物来确定生物活性的透明质酸。此外，我们将优化透明质酸的治疗剂量和治疗计划。在特异性目标2中，我们将研究透明质酸对亚致死照射后造血恢复的影响。由于在大量暴露于辐射的情况下，除了移植造血干细胞外，还需要治疗干预，因此我们将测试是否可以使用定义大小的HA聚合物来促进不同剂量照射后的造血恢复，而无需移植造血干细胞。此外，我们将测试不同的给药途径，包括口服和皮下给药。小鼠接受不同剂量（1Gy, 2Gy, 4Gy， 6Gy和8Gy）的亚致死照射，然后给予透明质酸。外周血成熟造血细胞和骨髓造血干细胞/祖细胞恢复的动态将被检查。获得的数据将为一种新的治疗方法提供基础，通过靶向造血生态位来对抗辐射诱导的全血细胞减少症。总的来说，这项拨款申请将使我们能够测试一个新的假设，并为进一步研究将透明质酸用作治疗剂的可能性提供数据。

DESCRIPTION (provided by applicant): Ionizing irradiation is harmful for many organs and tissues in the body, including the hematopoietic system. In addition to eliminating proliferating hematopoietic progenitors, irradiation affects the structure and function of the hematopoiesis-supportive niche. A lack of drugs, which normalize the function of the hematopoietic niche after ionizing irradiation, reflects gaps in our knowledge regarding fundamental stem cell biology and remains an obstacle to an optimal therapeutic approach. We have previously demonstrated that hyaluronan (HA) contributes to the structure of the hematopoietic niche in bone marrow and supports generation of all hematopoietic lineages. However, during the exposure to irradiation, HA undergoes chemical degradation, which contributes to the imbalance of hematopoietic homeostasis in the niche. This project will address the question of whether exogenous HA can be used to facilitate the recovery of hematopoiesis following various doses of irradiation. In Specific Aim 1, we will test the effects of HA on the recovery of hematopoiesis in mice subjected to lethal irradiation and bone marrow transplantation by monitoring the number of mature hematopoietic cells in peripheral blood and hematopoietic stem cells and committed progenitors in bone marrow. Since the biological effects of HA are determined by its size, we will identify biologically active HA by testing a panel of HA polymers of defined size. In addition, we will optimize the therapeutic dose of HA and treatment schedule. In Specific Aim 2, we will investigate the effect of HA on hematopoietic recovery following sub-lethal irradiation. Since in the scenario of massive exposure to irradiation, therapeutic interventions other then transplantation of hematopoietic stem cells are required, we will test whether the defined size HA polymers can be used to facilitate hematopoietic recovery following various doses of irradiation without transplantation of hematopoietic stem cells. In addition, we will test different drug administration routes including oral and subcutaneous. Mice will be sub-lethally irradiated with various doses (1Gy, 2Gy, 4Gy, 6Gy and 8Gy) followed by administration of HA. The dynamics of the recovery of mature hematopoietic cells in peripheral blood and hematopoietic stem/progenitor cells in bone marrow will be examined. Obtained data will provide a basis for a novel therapeutic approach to fight irradiation-induced pancytopenia by targeting the hematopoietic niche. Overall, this grant application will allow us to test a novel hypothesis and to generate data for further studies on the possibility to use HA as a therapeutic agent. PUBLIC HEALTH RELEVANCE: Hyaluronan (HA) has a potential to be developed as a drug to stimulate the recovery of peripheral blood cells in subjects exposed to various doses of ionizing irradiation. We will test the effects of HA on regeneration of bone marrow hematopoiesis in vivo following various doses of irradiation with or without hematopoietic stem cell support. Together, the obtained results will provide important information regarding the possibility to target the hematopoietic niche by using HA following different doses of ionizing irradiation.