Hyaluronan facilitates hematopoietic recovery following ionizing irradiation

透明质酸促进电离辐射后造血恢复

• 批准号: 7669928
• 负责人: SOPHIA K KHALDOYANIDI
• 金额: $ 39.57万
• 依托单位: CASCADE LIFESCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-17 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7669928
• 关键词: Address; Affect; Animals; Applications Grants; Biochemistry; Biological; Blood Cells; Blood Platelets; Bone Marrow; Bone Marrow Transplantation; Cells; Chemicals; Commit; Data; Dose; Drug Administration Routes; Erythrocytes; Experimental Models; Exposure to; Generations; Glycosaminoglycans; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Hyaluronan; Knowledge; Leukocytes; Military Personnel; Molecular Weight; Monitor; Multipotent Stem Cells; Mus; Natural regeneration; Oral; Organ; Pancytopenia; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Polymers; Proliferating; Protocols documentation; Recovery; Route; Small Business Technology Transfer Research; Spleen; Stem cells; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Tissues; Transplantation; Treatment Protocols; Umbilical cord structure; Water; Whole-Body Irradiation; base; depolymerization; drug candidate; fighting; food consumption; hematopoietic stem cell fate; improved; in vivo; irradiation; novel; novel therapeutic intervention; peripheral blood; progenitor; public health relevance; self-renewal; stem; stem cell biology; subcutaneous

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.

描述（由申请人提供）：电离辐射对体内许多器官和组织有害，包括造血系统。除了消除增殖的造血祖细胞外，辐射还影响造血支持生态位的结构和功能。缺乏药物，使电离辐射后造血小生境的功能正常化，反映了我们对基本干细胞生物学知识的差距，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，并支持所有造血谱系的产生。然而，在暴露于辐射期间，HA经历化学降解，这有助于在生态位中造血稳态的失衡。本项目将探讨外源性HA是否可用于促进不同剂量照射后造血功能的恢复。在特定目标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，检测HA对接受致死性辐射和骨髓移植的小鼠造血恢复的影响。由于HA的生物效应由其大小决定，因此我们将通过测试一组确定大小的HA聚合物来鉴定具有生物活性的HA。此外，我们将优化HA的治疗剂量和治疗方案。在特定目标2中，我们将研究HA对亚致死剂量照射后造血恢复的影响。由于在大量暴露于辐射的情况下，需要除造血干细胞移植之外的治疗干预，我们将测试确定尺寸的HA聚合物是否可用于在各种剂量的辐射后促进造血恢复而不移植造血干细胞。此外，我们将测试不同的给药途径，包括口服和皮下给药。小鼠将用不同剂量（1Gy、2Gy、4Gy、6 Gy和8 Gy）进行亚致死性辐照，然后施用HA。将检查外周血中成熟造血细胞和骨髓中造血干/祖细胞的恢复动力学。获得的数据将提供一个新的治疗方法，以打击辐射诱导的全血细胞减少症的基础上，针对造血生态位。总的来说，这项拨款申请将使我们能够测试一个新的假设，并为进一步研究使用HA作为治疗剂的可能性产生数据。 公共卫生关系：透明质酸（HA）有可能被开发为一种药物，以刺激暴露于各种剂量的电离辐射的受试者的外周血细胞的恢复。我们将测试HA对骨髓造血再生的影响，在体内不同剂量的照射后，有或没有造血干细胞的支持。总之，所获得的结果将提供重要的信息有关的可能性，通过使用HA后，不同剂量的电离辐射的造血生态位的目标。