Cord Blood Biomarkers for Engraftment

用于移植的脐带血生物标志物

基本信息

批准号：
8327157
负责人：
Kristin Page-Chartrand
金额：
$ 12.43万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8327157
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

项目摘要

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）：该提案描述了Kristin Page-Chartrand博士（PI）的全面职业发展计划，该计划是杜克大学医学中心儿科血液和骨髓移植计划的教职员工。 PI的长期职业目标是成为一名独立的医师科学家，在小儿移植和再生医学领域进行转化研究。她目前的提议着重于研究，这些研究应改善接受无关的供体脐带血移植（UCBT）的儿童的植入和结果。该候选人的环境非常出色，提供了独特的机会和资源来进行她的学习并增强她的职业发展。杜克大学医学中心是一个世界知名的学术医学中心，在基础，转化和临床研究方面具有长期的记录。她的导师乔安妮·库尔茨伯格（Joanne Kurtzberg）博士是UCBT和Cord Blood（CB）银行领域的先驱。咨询委员会组成的咨询委员会由UCBT，生物统计学和临床方法论的国家和国际专家组成，并既有成功地指导临床医生，从而为高产的研究职业提供了既定的记录。除了专家指导外，还开发了一项全面的课程，以提高临床试验设计和管理，生物统计学，CB处理和测试的技能。该建议还借鉴了PI容易获得的杜克大学医学中心的资源优势，包括儿科和成人移植计划，卡罗来纳斯脐带血库（CCBB），杜克干细胞实验室，杜克大学托管医学研究所，杜克大学临床研究所（DCRI），DCRI临床研究研究所，DCRI临床研究培训培训培训计划该研究提案着重于改善无关捐助者UCBT的预后的策略，该程序改善了整体移植的访问。 UCBT成功的主要障碍是主要的移植失败，该衰竭发生在多达20％的患者中。该提案的中心假设是，UCBT后的大部分移植失败是由于某些脐带血（CB）移植物的效力不足，而这些脐带血（CB）移植物无法通过当前的移植物选择标准（例如总成核细胞计数[TNC]和人类白细胞抗原[HLA]匹配）。当前，尚无脐带血库或移植中心接受的经过验证的测试或算法来选择脐带血单位（CBU）进行移植。最重要的是，该领域缺乏预测CB植入的效力测定，这可以指导CBU选择进行移植。 PI进行的初步研究表明，在CB移植物上测量的菌落形成单位（CFU）与UCBT后的中性粒细胞植入具有最高的相关性（P <0.0001），但该测定很长，很难标准化。酶醛脱氢酶（ALDH）的细胞表达是造血干细胞和祖细胞的标志物，可以从冷冻保存的CBU中进行测量，并且与CBU中的CFU含量具有很高的相关性。在该提案中，Page-Chartrand博士将研究基于细分市场的ALDHBR分析是否可以作为替代物或CFU测定法的辅助物，以及是否可以将其纳入下面描述的脐带血Apgar（CBA）中，从而增强其预测活性。该提案的主要目标是进一步验证称为Cord Blood Apgar（CBA）得分的加权评分系统。 CBA基于基于晶元的数据（前晶体），截止后数据和基于组合的透明前和截闻后数据的复合分数分配了三个分数。使用单个机构的患者的回顾性数据库创建并验证了CBA，并在骨髓性调节后接受单个非操纵的CBU，并根据几种移植特征的单变量分析，并根据危险比的大小进行加权。初步工作已经完成，但是在将CBA纳入临床实践之前需要进行预期验证。具体目的是：（1）使用外部的，较大的国际注册表数据库进一步验证脐带血Apgar作为植入的独立预测因子（（2），以确定是否可以通过确定CFU分析的ALDHBR含量来确定CFU测定法，并通过确定CBU效力并确定范围内的关系和（3）与Cryop Cagrop caryoperage caryop的关系（3）的关系，并（3） CCBB的UCBT。如果AIM 2的结果是有利的，则计划进一步探索在这些移植中向CBA添加ALDHBR含量的影响。