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

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病变。全身照射（TBI）和静脉化疗均可刺激造血恢复，包括通过增加A（1-7）治疗后的祖细胞增殖来减少血小板减少。在本应用中，我们将采用顺序方法来确定照射后小鼠的最佳剂量计划，确定照射后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：我们将首先建立电离辐射后刺激血小板浓度重建所需的A（1-7）的有效剂量范围。这将通过在辐射后第7、14、21和30天测量在a（1-7）剂量范围内建立60,000血小板/ l的最低点所需的辐射量的剂量减少系数来测量。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、隔天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。目的3：我们将确定照射和A（1-7）治疗之间的最大时间间隔(使用目标2中确定的最佳剂量计划来优化RIT的血小板恢复。所有药物都有一个最佳治疗窗口，包括剂量频率和辐射暴露与药物干预之间的最大允许间隔。目的4：我们将测试放射暴露后进入外周循环的血小板对A（1-7）治疗的生物学功能。目的5：我们假设A（1-7）介导的RIT恢复是通过激活MAS受体修饰骨髓中的巨核细胞谱系发生的。将进行研究以了解A（1-7）改变TBI后血小板恢复的机制。第一组研究将确定血管紧张素受体表达在有和没有A治疗的TBI中的变化（1-7）。进一步测定A（1-7）给药对完整小鼠和血管紧张素受体（包括MAS）敲除后巨核细胞祖细胞数量和巨核细胞（数量和倍性）的影响。本应用程序将开发一种旨在减轻放射后血小板减少症的产品。由于大量人口有可能意外或故意暴露于电离辐射，减轻这种暴露的副作用，如导致高发病率和死亡率的血小板减少症，是很重要的。

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.