Advancing Diagnostics and Therapeutics in Bone Marrow Failure

推进骨髓衰竭的诊断和治疗

• 批准号: 8898911
• 负责人: AMY E DEZERN
• 金额: $ 14.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8898911
• 关键词: Address; Adult; Advisory Committees; Affect; Age; Aplastic Anemia; Appointment; Biological; Biological Assay; Bone Marrow; Bone Marrow Transplantation; Child; Clinical; Clinical Research; Clinical Trials; Collaborations; Complication; Cyclophosphamide; Data; Diagnosis; Diagnostic; Disease; Dose; Dysmyelopoietic Syndromes; Faculty; Failure; Future; Genetic; Genetic Markers; Goals; Grant; Health; Hematologic Neoplasms; Hematology; Hospitals; Immune; Immune response; Immunologic Markers; Immunosuppression; Inherited; Length; Lymphocyte; Lymphocyte Subset; Marrow; Measurement; Measures; Mediating; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Modification; Morbidity - disease rate; Nature; Non-Malignant; Outcome; Pancytopenia; Patients; Procedures; Process; Prophylactic treatment; Publications; Refractory; Research; Research Personnel; Research Project Grants; Resources; Role; SECTM1 gene; Safety; Siblings; Syndrome; Techniques; Testing; Therapeutic; Therapeutic immunosuppression; Toxic effect; Transplantation; Universities; Ursidae Family; Work; bone; bone marrow failure syndrome; clinical application; clinical investigation; effective therapy; graft vs host disease; granulocyte; improved; medical schools; mortality; novel strategies; novel therapeutic intervention; oncology; professor; rat Piga protein; response; skills; standard of care; success; telomere

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.

描述（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，主要任命于血液恶性肿瘤科，次要任命于血液科。她之前曾获得 K12 补助金的支持，并完成了临床研究硕士学位。她的主要导师罗伯特·布罗德斯基 (Robert Brodsky) 博士是阵发性睡眠性血红蛋白尿 (PNH) 领域的领军人物，她的共同导师是领先的端粒生物学家玛丽·阿马尼奥斯 (Mary Armanios) 博士。她的博士顾问委员会。博罗维茨、库克、罗斯纳和琼斯都是临床试验和这些范例在骨髓衰竭中的应用方面的专家。 K23 奖项的支持将使 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资助的指导。 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。在此应用中，DeZern 博士正在研究 BMF（特别是再生障碍性贫血 (AA)）中免疫反应的作用，然后在对免疫抑制治疗无反应的患者中试验一种新的骨髓移植治疗方法。 PNH 克隆是免疫介导 AA 的标记。端粒长度短是遗传 BMF 的标志。结合起来，对 AA 患者进行这些检测测试可以预测谁更有可能对免疫抑制治疗产生反应。对于对免疫抑制没有反应的部分患者，我们必须有可用的治疗选择，而不受年龄或骨髓移植捐献者可用性的限制。 DeZern 博士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，以回答这两个问题。 (1)我们能否解释一下PNH克隆和端粒长度在AA中的意义？ (2) 我们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测量 AA 患者中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测试这些问题免疫抑制，以及（3）利用移植后试验对难治性严重 AA 患者进行单倍体相合供体骨髓移植的临床试验环磷酰胺可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，从而减少因治疗不当而导致的 AA 治疗相关发病率和死亡率。这将消除不必要的资源使用 血液学领域。