Hyaluronan facilitates hematopoietic recovery following ionizing irradiation

说明(申请人提供)：电离辐射对体内许多器官和组织有害，包括造血系统。除了清除增殖的造血祖细胞外，辐射还会影响支持造血的壁龛的结构和功能。缺乏在电离辐射后使造血龛功能正常化的药物，反映了我们对基础干细胞生物学知识的空白，并仍然是最佳治疗方法的障碍。我们以前已经证明，透明质酸(HA)有助于骨髓中造血生态位的结构，并支持所有造血系的生成。然而，在照射过程中，HA经历了化学降解，这导致了生态位中造血平衡的失衡。该项目将解决外源性HA是否可用于促进不同剂量照射后的造血恢复的问题。在具体目标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定向祖细胞的数量来测试HA对致死照射和骨髓移植后小鼠造血恢复的影响。由于HA的生物效应是由其大小决定的，我们将通过测试一组定义大小的HA聚合物来鉴定具有生物活性的HA。此外，我们还将优化HA的治疗剂量和治疗方案。在特定的目标2中，我们将研究HA对亚致死剂量照射后的造血恢复的影响。由于在大量照射的情况下，除了移植造血干细胞外，还需要进行其他治疗干预，我们将测试在不同剂量的照射后，在不移植造血干细胞的情况下，是否可以使用定义尺寸的HA聚合物来促进造血恢复。此外，我们还将测试不同的给药途径，包括口服和皮下给药。小鼠将接受不同剂量(1GY、2GY、4GY、6GY和8GY)的亚致死剂量照射，然后注射HA。将检测外周血中的成熟造血细胞和骨髓中的造血干/祖细胞的恢复动态。所获得的数据将为一种新的治疗方法提供基础，通过靶向造血利基来对抗辐射引起的全血细胞减少症。总体而言，这项拨款申请将使我们能够检验一项新的假设，并为进一步研究使用HA作为治疗剂的可能性产生数据。 公共卫生相关性：透明质酸(HA)有潜力被开发为一种药物，以刺激暴露在不同剂量的电离辐射下的受试者的外周血细胞恢复。我们将在体内测试HA在不同剂量照射后，在有或没有造血干细胞支持的情况下对骨髓造血再生的影响。总之，所获得的结果将提供关于在不同剂量的电离辐射后使用HA靶向造血生态位的可能性的重要信息。

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.