Advancing Diagnostics and Therapeutics in Bone Marrow Failure

项目摘要 艾米·德泽恩博士是约翰·霍普金斯大学医学院肿瘤学助理教授 在恶性血液病科有一项主要任命，在 血液科。她之前得到了K12奖学金的支持，并在 临床调查。她的主要导师罗伯特·布罗斯基博士是突发性研究发现的领导者。 她的共同导师是玛丽·阿玛尼奥斯博士，她是一位领先的端粒生物学家。她 博洛维茨、库克、罗斯纳和琼斯博士的顾问委员会都是临床试验和 这些范例在骨髓衰竭中的应用。K23奖项的支持将使Dezern博士能够 获得额外的研究技能，并在撰写出版物和开发研究拨款方面获得指导 在执行她的研究项目时。S博士的目标是成为一名独立的调查员和领导者 在骨髓衰竭(BMF)临床研究中。在这项应用中，德泽恩博士正在研究免疫的作用 对BMF的反应，特别是再生障碍性贫血(AA)，然后试验一种新的骨骼治疗方法 对免疫抑制治疗无效的患者进行骨髓移植。PNH克隆是一种 免疫介导性再生障碍性贫血的标志物。短端粒长度是遗传性BMF的标志。结合使用，测试 这些针对再生障碍性贫血患者的检测可以预测谁更有可能对免疫抑制治疗有反应。 对于对免疫抑制无反应的那部分患者，我们必须有一个治疗选择， 是可用的，不受年龄或骨髓移植捐赠者可用性的限制。德泽恩博士已经产生了 重要的初步数据和整个约翰·霍普金斯医院的合作 这两个相关的问题。(1)我们能解释PNH克隆和端粒长度在再障中的意义吗？ (2)我们能否提高免疫抑制治疗无效的再生障碍性贫血患者的存活率？她将对这些进行测试 问题：(1)回顾分析再生障碍性贫血患者的PNH克隆，并将其与对 免疫抑制(2)前瞻性测量粒细胞和淋巴细胞的端粒长度 再生障碍性贫血患者的临床验证方法及其与免疫抑制反应的相关性，以及(3) 半相合供者骨髓移植治疗难治性白血病的临床试验 重症再生障碍性贫血移植后应用环磷酰胺减少移植物抗宿主并发症 疾病。这项研究的结果将支持未来关于预测免疫抑制的生物学相关性的工作 治疗反应和治疗改进，从而降低与AA治疗相关的发病率和死亡率 不恰当的待遇。这将消除血液学领域不必要的资源利用。

PROJECT ABSTRACT Dr. Amy DeZern is an Assistant Professor of Oncology at The Johns Hopkins University School of Medicine with a primary appointment in the division of Hematologic Malignancies and a secondary appointment in the division of Hematology. She has previously been supported on a K12 grant and has completed a Masters in Clinical Investigation. Her primary mentor, Dr. Robert Brodsky, is a leader in discoveries in paroxysmal nocturnal hemoglobinuria (PNH), and her co-mentor is Dr. Mary Armanios, a leading telomere biologist. Her advisory committee of Drs. Borowitz, Cooke, Rosner and Jones are all faculty experts in clinical trials and application of these paradigms to bone marrow failure. Support from the K23 award will enable Dr. DeZern to gain additional research skills and receive mentorship in authoring publications and developing research grants while performing her research project. Dr. DeZern¿s goal is to become an independent investigator and leader in bone marrow failure (BMF) clinical research. In this application, Dr. DeZern is studying the role of immune response in BMF, specifically aplastic anemia (AA), and then piloting a novel therapeutic approach to bone marrow transplant in patients who are not responsive to immunosuppressive therapy. PNH clones are a marker of immune-mediated AA. Short telomere length is a marker of genetic BMF. In combination, testing of these assays for patients with AA may predict who is more likely to respond to immunosuppressive therapy. For the portion of patients who do not respond to immunosuppression, we must have a therapeutic option that is available, not limited by age or availability of a donor for bone marrow transplant. Dr. DeZern has generated significant preliminary data and developed collaborations throughout the Johns Hopkins Hospital to answer these two related questions. (1) Can we explain the significance of PNH clones and telomere lengths in AA? and (2) Can we increase survival for AA patients refractory to immunosuppressive therapy? She will test these questions by (1) retrospectively analyzing the PNH clones of patients with AA and correlating it to response to immunosuppression (2) prospectively measuring telomere lengths in granulocytes and lymphocytes by the clinically validated method in patients with AA and correlating it to response to immunosuppression, and (3) piloting a clinical trial of bone marrow transplantation from haplo-identical donors in patients with refractory severe AA using post transplantation cyclophosphamide to decrease the complications of graft versus host disease. Results of this research will support future work on biological correlates to predict immunosuppressive therapy response and therapy modification, thereby reducing AA treatment-related morbidity and mortality from inappropriate treatment. This will eliminate unnecessary resource utilization in the field of hematology.