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，包括用A（1-7）治疗后通过增加祖细胞增殖减少血小板减少。在本申请中，我们将采用序贯方法来确定照射后小鼠的最佳剂量方案，确定A（1-7）有效降低RIT的照射后时间窗，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。这些研究的目标和实验方法如下：目标1：我们将首先确定刺激电离辐射后血小板浓度重建所需的A（1-7）的有效剂量范围。这将通过建立辐射量的剂量减少因子来测量，该辐射量是在辐射后第7、14、21和30天测量的A（1-7）剂量范围内建立60，000血小板/μ l的最低值所需的。目标二：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提供了辐射暴露后血小板恢复的最佳应答。目标三：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中确定的最佳剂量方案，以优化RIT中的血小板回收率）。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。目标4：我们将检测辐射暴露后进入外周循环的血小板对A（1-7）治疗的反应的生物学功能。目标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TBI伴或不伴A治疗时血管紧张素受体表达的变化（1-7）。此外，将测定A（1-7）给药对完整和血管紧张素受体（包括MAS）敲除小鼠中巨核祖细胞和巨核细胞的数量（数量和倍性）的影响。该申请将开发一种旨在缓解辐射后血小板减少症的产品。由于大量人口意外或故意暴露于电离辐射的威胁，减轻这种暴露的副作用，如血小板减少症，造成高发病率和死亡率是非常重要的。

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.