Advancing Diagnostics and Therapeutics in Bone Marrow Failure

项目摘要 博士Amy DeZern是约翰霍普金斯大学医学院的肿瘤学助理教授 主要预约在血液肿瘤科，次要预约在 血液科。她以前曾获得K12资助，并在2009年完成了硕士学位。 临床研究。她的主要导师，罗伯特·布罗茨基博士，是一个领导者，发现在阵发性 她的共同导师是著名的端粒生物学家玛丽阿马尼奥斯博士。她 由Borowitz、Cooke、Rosner和Jones博士组成的咨询委员会都是临床试验方面的专家， 将这些范例应用于骨髓衰竭。K23奖的支持将使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赠款方面接受指导 在进行她的研究项目时DeZern博士的目标是成为一名独立的研究者和领导者。 骨髓衰竭（BMF）的临床研究。在这个应用程序中，DeZern博士正在研究免疫的作用， BMF的反应，特别是再生障碍性贫血（AA），然后引导一种新的治疗方法，以骨 对免疫抑制治疗无反应的患者进行骨髓移植。PNH克隆是一种 免疫介导AA的标志物。短端粒长度是遗传性BMF的标志。结合起来，测试 对AA患者的这些测定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患者，我们必须有一种治疗选择， 是可用的，不受年龄或骨髓移植供体的可用性的限制。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？她会测试这些 （1）回顾性分析AA患者的PNH克隆，并将其与对 免疫抑制（2）通过免疫细胞化学方法前瞻性地测量粒细胞和淋巴细胞中的端粒长度。 在AA患者中的临床验证方法，并将其与免疫抑制反应相关联，以及（3） 半相合供者骨髓移植治疗难治性骨髓瘤的临床试验 严重再障移植后应用环磷酰胺减少移植物抗宿主病并发症 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，从而降低AA治疗相关的发病率和死亡率， 不适当的待遇。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.