Cord Blood Biomarkers for Engraftment

用于移植的脐带血生物标志物

• 批准号: 8677620
• 负责人: Kristin Page-Chartrand
• 金额: $ 13.37万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677620
• 关键词: Academic Medical Centers; Address; Adult; Advisory Committees; Algorithms; Apgar Score; Basic Science; Biological Assay; Biological Markers; Biometry; Blood; Blood Banks; Blood donor; CD34 gene; Cell Count; Cells; Characteristics; Child; Childhood; Clinical; Clinical Research; Clinical Trials; Clinical Trials Design; Colony-Forming Units Assay; Colony-forming units; Companions; Cryopreservation; Data; Databases; Development Plans; Disease; Dose; Educational Curriculum; Engraftment; Environment; Enzymes; Event; Faculty; Flow Cytometry; Freezing; Goals; Guidelines; HLA Antigens; Hematopoietic; Hereditary Disease; Hour; Immunologic Deficiency Syndromes; Improve Access; Institutes; Institution; International; Laboratories; Learning; Life; Malignant Neoplasms; Marrow; Measures; Mentors; Methodology; Methods; Minority; Names; Outcome; Pancytopenia; Patients; Physicians; Pilot Projects; Positioning Attribute; Procedures; Process; Regenerative Medicine; Registries; Research; Research Institute; Research Proposals; Research Training; Resources; Sampling; Scientist; Selection Criteria; Shipping; Ships; Sickle Cell Anemia; Specificity; Staging; Stem cells; Surrogate Markers; System; Testing; Training Programs; Translational Research; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Unit of Measure; Validation; Weight; Work; aldehyde dehydrogenases; base; career; career development; clinical practice; conditioning; graft failure; hazard; improved; leukemia; member; neutrophil; programs; prospective; skills; stem; success; translational medicine; translational study; transplantation medicine

DESCRIPTION (provided by applicant): This proposal describes a comprehensive career development plan for Dr. Kristin Page-Chartrand (PI), a faculty member in the Division of Pediatric Blood and Marrow Transplant Program at Duke University Medical Center. The long term career goal of the PI is to become an independent physician scientist conducting translational research in the fields of pediatric transplantation and regenerative medicine. Her current proposal focuses on studies that should result in improved engraftment and outcomes for children undergoing unrelated donor umbilical cord blood transplantation (UCBT). The environment for this candidate is outstanding, providing unique opportunities and resources to conduct her studies and to enhance her career development. Duke University Medical Center is a world renowned academic medical center with a long-standing track record in basic, translational and clinical research. Her mentor, Dr. Joanne Kurtzberg is a pioneer in the field of UCBT and cord blood (CB) banking. The advisory committee assembled is comprised of national and international experts in UCBT, biostatistics and clinical methodology with an established record of successfully mentoring clinician-scientists to highly productive research careers. In addition to expert mentoring, a comprehensive curriculum has been developed to enhance skills in clinical trial design and management, biostatistics, CB processing and testing. This proposal also draws on the strengths of resources at Duke University Medical Center readily available to the PI including the Pediatric and Adult transplant programs, the Carolinas Cord Blood Bank (CCBB), the Duke Stem Cell Laboratory, the Duke Translational Medicine Institute, the Duke Clinical Research Institute (DCRI), the DCRI Clinical Research Training Program, Aldagen Inc, and the EMMES Corporation. The research proposal focuses on strategies to improve outcomes of unrelated donor UCBT, a procedure that has improved overall access to transplantation. The major obstacle to the success of UCBT is primary graft failure, which occurs in up to 20% of patients. The central hypothesis of this proposal is that a significant portion of graft failure after UCBT is due to inadequate potency of some cord blood (CB) grafts that is not adequately assessed by current graft selection criteria (e.g. total nucleated cell count [TNC] and Human Leukocyte Antigen [HLA] matching). Currently, there are no standardized practices, validated tests or algorithms accepted by cord blood banks or transplant centers to select cord blood units (CBUs) for transplantation. Most importantly, the field lacks potency assays predictive of CB engraftment that could guide CBU selection for transplantation. Preliminary studies performed by the PI showed that colony forming units (CFUs), measured on the CB graft have the highest correlation with neutrophil engraftment after UCBT (p<0.0001), but this assay is lengthy and hard to standardize. Cellular expression of the enzyme aldehyde dehydrogenase (ALDH) is a marker of hematopoietic stem and progenitor cells that can be measured in a segment from a cryopreserved CBU and has a high correlation with CFU content in a CBU. In this proposal, Dr. Page-Chartrand will investigate whether the segment based ALDHbr assay can serve as a surrogate or as an adjunct to the CFU assay and also whether it can be incorporated into in the Cord Blood Apgar (CBA) described below, strengthening its predictive activity. The major goal of this proposal is to further validate a weighted scoring system named the Cord Blood Apgar (CBA) score. The CBA assigns three scores to a CBU based on pre-cryopreserved data (pre-cryo), post-thaw data, and a composite score based on combined pre-cryo and post-thaw data. The CBA was created and validated using a retrospective database of patients at a single institution receiving a single, non- manipulated CBU after myeloablative conditioning with the weighting based on the magnitude of the hazard ratios in univariate analysis of several graft characteristics. Preliminary work has been completed but a prospective validation is required before incorporating the CBA into clinical practice. The specific aims are to: (1) to further validate the Cord Blood Apgar as an independent predictor of engraftment using an external, larger international registry database, (2) to determine whether ALDHbr content assayed on an attached segment can substituted for the CFU assay in determining CBU potency and determine the relationship between the segment and the product in the cryopreservation bag, and (3) to prospectively validate the CBA by studying units released for UCBT from the CCBB. If results from Aim 2 are favorable, further exploration into the impact of adding ALDHbr content to the CBA in these transplants is planned.

描述（由申请人提供）：本提案描述了杜克大学医学中心儿科血液和骨髓移植项目部教员 Kristin Page-Chartrand 博士 (PI) 的全面职业发展计划。 PI 的长期职业目标是成为一名独立的医师科学家，在儿科移植和再生医学领域进行转化研究。她目前的提案重点是那些应改善接受无关捐赠者脐带血移植（UCBT）的儿童的植入和结果的研究。该候选人的环境非常优越，为她的学习和职业发展提供了独特的机会和资源。杜克大学医学中心是世界著名的学术医学中心，在基础、转化和临床研究方面拥有悠久的历史记录。她的导师 Joanne Kurtzberg 博士是 UCBT 和脐带血 (CB) 银行领域的先驱。咨询委员会由 UCBT、生物统计学和临床​​方法学领域的国内和国际专家组成，他们在成功指导临床医生科学家开展高产的研究职业方面拥有良好的记录。除了专家指导外，还开发了综合课程，以提高临床试验设计和管理、生物统计学、CB 处理和测试方面的技能。该提案还利用了杜克大学医学中心可供 PI 使用的资源优势，包括儿科和成人移植项目、卡罗来纳州脐带血库 (CCBB)、杜克干细胞实验室、杜克转化医学研究所、杜克大学临床研究所 (DCRI)、DCRI 临床研究培训计划、Aldagen Inc 和 EMMES Corporation。该研究提案的重点是改善无关捐赠者 UCBT 的结果的策略，该程序改善了整体移植的机会。 UCBT 成功的主要障碍是原发性移植失败，高达 20% 的患者会发生这种情况。该提案的中心假设是，UCBT 后移植失败的很大一部分是由于某些脐带血 (CB) 移植物效力不足，而当前的移植物选择标准（例如总有核细胞计数 [TNC] 和人类移植物）未充分评估这些移植物的效力。白细胞抗原 [HLA] 匹配）。目前，脐带血库或移植中心没有接受标准化的做法、经过验证的测试或算法来选择用于移植的脐带血单位（CBU）。最重要的是，该领域缺乏预测 CB 植入的效力测定，无法指导 CBU 移植选择。 PI 进行的初步研究表明，在 CB 移植物上测量的集落形成单位 (CFU) 与 UCBT 后中性粒细胞植入的相关性最高 (p<0.0001)，但该测定法冗长且难以标准化。乙醛脱氢酶 (ALDH) 的细胞表达是造血干细胞和祖细胞的标志物，可以在冷冻保存的 CBU 的片段中进行测量，并且与 CBU 中的 CFU 含量具有高度相关性。在此提案中，Page-Chartrand 博士将研究基于片段的 ALDHbr 检测是否可以作为 CFU 检测的替代或辅助，以及是否可以将其纳入下文所述的脐带血 Apgar (CBA) 中，从而加强它的预测活动。 该提案的主要目标是进一步验证名为脐带血阿普加（CBA）评分的加权评分系统。 CBA 根据冷冻前数据（冷冻前）、解冻后数据以及基于冷冻前和解冻后数据组合的综合分数，为 CBU 分配三个分数。 CBA 是使用单一机构的患者回顾性数据库创建和验证的，这些患者在清髓性调理后接受单一非操纵性 CBU，并根据多个移植特征的单变量分析中的风险比大小进行加权。初步工作已经完成，但在将 CBA 纳入临床实践之前需要进行前瞻性验证。具体目标是：(1) 使用外部更大的国际注册数据库进一步验证脐带血 Apgar 作为植入的独立预测因子，(2) 确定在附着片段上测定的 ALDHbr 含量是否可以替代 CFU 测定确定 CBU 效力并确定冷冻保存袋中的片段与产品之间的关系，以及 (3) 通过研究 CCBB 发布的 UCBT 单位来前瞻性验证 CBA。如果目标 2 的结果良好，则计划进一步探索在这些移植中向 CBA 添加 ALDHbr 内容的影响。