Advancing Diagnostics and Therapeutics in Bone Marrow Failure

描述（由申请人提供）：Amy DeZern博士是约翰霍普金斯大学医学院的肿瘤学助理教授，主要负责血液肿瘤科，次要负责血液科。她以前一直支持K12补助金，并已完成临床研究硕士学位。她的主要导师Robert Brodsky博士是阵发性睡眠性血红蛋白尿症（PNH）发现的领导者，她的共同导师是领先的端粒生物学家玛丽Armanios博士。她的顾问委员会由Borowitz、Cooke、Rosner和Jones博士组成，他们都是临床试验和将这些范例应用于骨髓衰竭的专家。来自K23奖的支持将使DeZern博士能够获得额外的研究技能，并在执行研究项目的同时获得撰写出版物和开发研究赠款的指导。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型骨髓移植治疗方法。PNH克隆是免疫介导的AA的标志物。短端粒长度是遗传性BMF的标志。结合起来，对AA患者进行这些检测可以预测谁更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选择，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来回答这两个相关问题。(1)我们能解释PNH克隆和端粒长度在AA中的意义吗？（2）我们能否提高免疫抑制治疗无效的再障患者的生存率？她将通过以下方式测试这些问题：（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，前瞻性测量AA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）开展单倍型骨髓移植的临床试验。同种供者移植后应用环磷酰胺减少难治性重症再障移植物抗宿主并发症疾病这项研究的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调整，从而减少AA治疗相关的发病率和死亡率不适当的治疗。这将消除不必要的资源利用， 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.