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: 8058309
• 负责人: KATHLEEN E. RODGERS
• 金额: $ 43.16万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058309
• 关键词: Adverse effects; Aftercare; Angiotensin Receptor; Biological Process; Blood Circulation; Blood Platelets; Bone Marrow; Dose; Drug Exposure; Frequencies; Hematopoietic; Intervention; Intravenous; Ionizing radiation; Knockout Mice; Lesion; Measurement; Measures; Mediating; Megakaryocytes; Modification; Morbidity - disease rate; Mus; Peripheral; Pharmaceutical Preparations; Ploidies; Population; Radiation; Recovery; Schedule; Testing; Therapeutic; Thrombocytopenia; Time; Whole-Body Irradiation; chemotherapy; 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（由应用提供）：A（1-7）刺激造血恢复，包括血小板减少症，并减少静脉化疗后的粘膜病变。刺激造血恢复，包括在总体照射（TBI）和静脉内化疗后，通过A（1-7）处理后的祖细胞增生减少血小板减少症。在此应用中，我们将采用一种顺序方法来定义辐照后小鼠中最佳剂量 - 链，确定辐射后的时间窗口（1-7）有效地减少RIT，评估血小板的生物学功能，该血小板在（1-7）治疗后进入外周血的生物学功能，并在A（1-7）治疗后进一步表征ACTION ACTICE机制（1-7）。这些研究和实验方法的对象如下：目标1：我们将首先建立刺激电离辐射后刺激血小板浓度重建所需的有效剂量范围。这将通过确定建立60,000血小板的辐射量的剂量还原系数来衡量，目的2：使用目标1中确定的每周剂量，我们将确定每日剂量，替代日给药还是每周两次剂量，或每周两次剂量提供了辐射后血小板恢复后的最佳响应。目标3：我们将确定辐射和（1-7）处理之间的最大时间间隔（使用最佳剂量时间表目标2来优化血小板从RIT中的恢复。所有药物具有最佳的治疗窗口，包括剂量的频率和剂量的频率以及在辐射暴露和药物干预之间的最大允许间隔。暴露。我们假设A（1-7）从RIT中介导的恢复是通过激活MAS受体来修饰骨髓中的骨骼。此外，将确定（1-7）给药对完整和血管紧张素受体（包括MAS）敲除小鼠的巨核细胞祖细胞和巨核细胞数量（数量和倍性）的影响。该应用程序将开发旨在减轻放射后血小板减少症的产品。随着大量人群意外或故意暴露于电离辐射的威胁，减轻暴露的副作用（例如血小板减少症）引起高度的发病率和死亡率是重要的。

项目成果

Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation.

• DOI: 10.3109/09553002.2012.676228
• 发表时间: 2012-06
• 期刊: International journal of radiation biology
• 影响因子: 2.6
• 作者: Rodgers KE;Espinoza T;Roda N;Meeks CJ;Hill C;Louie SG;Dizerega GS
• 通讯作者: Dizerega GS

Angiotensin-(1-7) synergizes with colony-stimulating factors in hematopoietic recovery.

血管紧张素-(1-7) 在造血恢复中与集落刺激因子协同作用。

• DOI: 10.1007/s00280-013-2312-9
• 发表时间: 2013
• 期刊: Cancer chemotherapy and pharmacology
• 影响因子: 3
• 作者: Rodgers,KathleenE;Espinoza,TheresaB;Roda,Norma;Meeks,ChristopherJ;diZerega,GereS
• 通讯作者: diZerega,GereS