A(1-7)-Mediated Mitigation of Radiation Induced Thrombocytopenia

A(1-7)-介导的辐射诱导的血小板减少症的缓解

• 批准号: 7552457
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 90.74万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-04 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7552457
• 关键词: Adverse effects; Aftercare; Angiotensin Receptor; Biological Process; Blood Circulation; Blood Platelets; Bone Marrow; Daily; Dose; Drug Exposure; Frequencies; Hematopoietic; Intervention; Intravenous; Ionizing radiation; Knockout Mice; Lesion; Measurement; Measures; Mediating; Megakaryocytes; Modification; Morbidity - disease rate; Mus; Numbers; Peripheral; Pharmaceutical Preparations; Ploidies; Population; Radiation; Range; Recovery; Schedule; Testing; Therapeutic; Thrombocytopenia; Time; Week; Whole-Body Irradiation; chemotherapy; day; dosage; irradiation; mortality; peripheral blood; progenitor; receptor; receptor expression; reconstitution; research study; response; time interval

DESCRIPTION (provided by applicant): A(1-7) stimulates hematopoietic recovery, including thrombocytopenia, and reduces mucosal lesions after intravenous chemotherapy. Stimulation of hematopoietic recovery including reduction of thrombocytopenia through increased progenitor proliferation after treatment with A(1-7) occurs after both total-body irradiation (TBI) and intravenous chemotherapy. In this application, we will employ a sequential approach to define the optimal dose-schedule in mice after irradiation, determine the window of time following radiation when A(1-7) is effective in reducing RIT, assess the biological function of platelets that enter the peripheral blood after A(1-7) therapy and further characterize the mechanisms of action whereby A(1-7) reduces RIT. The objectives for these studies and experimental approaches are listed below: Objective 1: We will first establish the effective dose range of A(1-7) required to stimulate reconstitution of platelet concentrations after ionizing radiation. This will be measured by establishing the dose reduction factor for the amount of radiation required to establish a nadir of 60,000 platelets/¿l over a range of doses of A(1-7) with measurements at days 7, 14, 21 and 30 after radiation. Objective 2: Using the total weekly dose determined in Objective 1, we will determine if divided daily dosing, alternate day dosing, or twice per week dosing provides the optimal response of platelet recovery following radiation exposure. Objective 3: We will determine the maximum time interval between irradiation and A(1-7) treatment (using the optimal dose schedule determined in Objective 2 to optimize platelet recovery from RIT. All drugs share an optimal therapeutic window encompassing frequency of dosage and maximum allowable interval between radiation exposure and drug intervention. Objective 4: We will test the biological function of platelets that enter the peripheral circulation in response to A(1-7) therapy following radiation exposure. Objective 5: We hypothesize that the A(1-7) mediated recovery from RIT occurs through modification of megakaryocytic lineages in the bone marrow through activation of the MAS receptor. Studies will be conducted to understand the mechanism by which A(1-7) modifies platelet recovery after TBI. The first set of studies will establish alterations in angiotensin receptors expression by TBI with and without treatment with A(1-7). Further, the effect of A(1-7) administration on the number of megakaryocyte progenitors and megakaryocytes (number and ploidy) after in intact and angiotensin receptor (including MAS) knock out mice will be determined. This application will develop a product aimed at the mitigation of post-radiation thrombocytopenia. With the threat of accidental or deliberate exposure of large populations to ionizing radiation, mitigation of side effects of such exposure, such as thrombocytopenia, that cause high degrees of morbidity and mortality is of importance.

描述（由申请人提供）：A(1-7)刺激造血恢复，包括血小板减少，并减少静脉化疗后的粘膜损伤。全身照射（TBI）和静脉化疗后，用A（1-7）治疗后会刺激造血恢复，包括通过增加祖细胞增殖来减少血小板减少症。在此应用中，我们将采用序贯方法来确定小鼠辐射后的最佳剂量方案，确定辐射后 A(1-7) 有效降低 RIT 的时间窗口，评估 A(1-7) 治疗后进入外周血的血小板的生物学功能，并进一步表征 A(1-7) 降低 RIT 的作用机制。这些研究和实验方法的目标如下： 目标 1：我们将首先确定电离辐射后刺激血小板浓度重建所需的 A(1-7) 有效剂量范围。这将通过确定在 A(1-7) 剂量范围内建立 60,000 个血小板/l 最低点所需的辐射量的剂量减少因子来测量，并在辐射后第 7、14、21 和 30 天进行测量。目标 2：使用目标 1 中确定的每周总剂量，我们将确定每日分次给药、隔日给药或每周两次给药是否能提供辐射暴露后血小板恢复的最佳反应。目标 3：我们将确定辐射和 A(1-7) 治疗之间的最大时间间隔（使用目标 2 中确定的最佳剂量方案来优化 RIT 中的血小板恢复。所有药物都有一个最佳治疗窗口，包括剂量频率以及辐射暴露和药物干预之间的最大允许间隔。目标 4：我们将测试 A(1-7) 治疗后进入外周循环的血小板的生物学功能 辐射暴露。目标 5：我们假设 A(1-7) 介导的 RIT 恢复是通过激活 MAS 受体来改变骨髓中的巨核细胞谱系而发生的。将进行研究以了解 A(1-7) 改变 TBI 后血小板恢复的机制。第一组研究将确定接受或不接受 TBI 治疗时血管紧张素受体表达的变化。 答（1-7）。此外，将测定A(1-7)施用对完整小鼠和血管紧张素受体(包括MAS)敲除小鼠中巨核细胞祖细胞和巨核细胞数量(数量和倍性)的影响。该申请将开发一种旨在缓解放射后血小板减少症的产品。由于大量人口意外或故意接触的威胁 电离辐射，减轻这种暴露的副作用，例如导致高发病率和死亡率的血小板减少症，非常重要。