Advancing Diagnostics and Therapeutics in Bone Marrow Failure

简介（由申请人提供）：Amy DeZern博士是约翰霍普金斯大学医学院肿瘤学助理教授，主要负责血液恶性肿瘤部门，次要负责血液部门。她曾获得K12资助，并完成了临床研究硕士学位。她的主要导师Robert Brodsky博士是发现突发性夜间血红蛋白尿（PNH）的领导者，她的共同导师Mary Armanios博士是一位领先的端粒生物学家。她的顾问委员会的博士。Borowitz, Cooke， Rosner和Jones都是临床试验和这些范例应用于骨髓衰竭的教员专家。K23奖的支持将使DeZern博士能够获得额外的研究技能，并在执行她的研究项目时获得撰写出版物和开发研究资助方面的指导。DeZern博士的目标是成为骨髓衰竭（BMF）临床研究的独立研究者和领导者。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），然后在对免疫抑制治疗无反应的患者中试行一种新的骨髓移植治疗方法。PNH克隆是免疫介导的AA的标志物。端粒长度短是遗传BMF的标志。综合起来，对AA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。对于免疫抑制无效的部分患者，我们必须有一个可用的治疗方案，不受年龄或骨髓移植供体的限制。DeZern博士已经生成了重要的初步数据，并在整个约翰霍普金斯医院开展了合作，以回答这两个相关的问题。(1)能否解释PNH克隆和端粒长度在AA中的意义？(2)能否提高免疫抑制治疗难治性AA患者的生存率？她将通过(1)回顾性分析AA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AA患者的粒细胞和淋巴细胞的端粒长度，并将其与免疫抑制反应相关联，来验证这些问题。(3)开展难治性重度AA患者单倍体相同供体骨髓移植的临床试验，移植后使用环磷酰胺减少移植物抗宿主病的并发症。该研究结果将支持未来的生物学相关工作，以预测免疫抑制治疗反应和治疗修改，从而降低AA治疗相关的不适当治疗的发病率和死亡率。这将消除不必要的资源利用

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.