Advancing Diagnostics and Therapeutics in Bone Marrow Failure

简介(申请人提供)：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，在血液恶性肿瘤科担任初级职务，在血液科担任二级职务。她之前得到了K12的资助，并已完成了临床调查硕士学位。她的主要导师罗伯特·布罗斯基博士是发现阵发性睡眠性血红蛋白尿(PNH)的领军人物，她的共同导师是著名的端粒生物学家玛丽·阿玛尼奥斯博士。她的顾问委员会博洛维茨博士、库克博士、罗斯纳博士和琼斯博士都是临床试验和将这些范例应用于骨髓衰竭的教职专家。K23奖项的支持将使Dezern博士能够获得更多的研究技能，并在执行她的研究项目的同时，在撰写出版物和开发研究补助金方面获得指导。Dezern博士的目标是成为骨髓衰竭(BMF)临床研究的独立研究员和领导者。在这项应用中，Dezern博士正在研究免疫反应在BMF中的作用，特别是再生障碍性贫血(AA)，然后试验一种新的治疗方法，用于对免疫抑制治疗无效的患者进行骨髓移植。PNH克隆是免疫介导型再生障碍性贫血的标志物。短端粒长度是遗传性BMF的标志。结合起来，对再生障碍性贫血患者进行这些检测可以预测谁更有可能对免疫抑制治疗有反应。对于部分对免疫抑制无反应的患者，我们必须有一种可用的治疗选择，而不是受年龄或骨髓移植捐赠者可用性的限制。德泽恩博士已经生成了重要的初步数据，并在约翰·霍普金斯医院建立了合作关系，以回答这两个相关问题。(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？她将通过以下方式测试这些问题：(1)回顾分析再生障碍性贫血患者的PNH克隆并将其与免疫抑制反应相关联；(2)通过临床验证的方法前瞻性地测量再生障碍性贫血患者粒细胞和淋巴细胞中的端粒长度，并将其与免疫抑制反应相关联；(3)在难治性重症再生障碍性贫血患者中进行一项半相合供者骨髓移植的临床试验，使用移植后的环磷酰胺来减少移植物抗宿主病的并发症。这项研究的结果将支持未来在生物相关性方面的工作，以预测免疫抑制治疗的反应和治疗改进，从而减少与AA治疗相关的发病率和因治疗不当而导致的死亡率。这将消除不必要的资源使用 血液学领域。

DESCRIPTION (provided by applicant): 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 failur. 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.