Bone Deficits and Excess Adiposity after Pediatric Bone Marrow Transplantation

儿童骨髓移植后的骨缺损和过度肥胖

• 批准号: 8670701
• 负责人: Sogol Mostoufi-Moab
• 金额: $ 16.5万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-04 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8670701
• 关键词: Acute Lymphocytic Leukemia; Adipose tissue; Adolescent; Advisory Committees; Age; Amines; Award; Benign; Biometry; Body Composition; Body fat; Bone Density; Bone Marrow; Bone Marrow Transplantation; Cancer Center; Cancer Survivor; Cancer Survivorship; Cell Culture Techniques; Center for Translational Science Activities; Child; Childhood; Childhood Cancer Survivor Study; Chronic Disease; Clinical Research; Clinical Trials; Clinical Trials Design; Complement; Complex; Complication; Critical Illness; Data; Data Analyses; Deterioration; Development Plans; Diabetes Mellitus; Dimensions; Disease; Endocrinologist; Endocrinology; Enrollment; Epidemiology; Evolution; Exposure to; Fatty acid glycerol esters; Feasibility Studies; Foundations; Funding; Future; Glucocorticoids; Goals; Grant; Growth; Health; Hematological Disease; Hematopoietic Stem Cell Transplantation; Hormones; Human; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Intervention Trial; Logic; Long-Term Survivors; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Manuscripts; Marrow; Measures; Mentors; Mesenchymal; Mesenchyme; Metabolic; Metabolic syndrome; Mortality Decline; Mus; Muscle; Obesity; Oncologist; Osteoblasts; Osteocytes; Osteogenesis; Outcome; Participant; Patients; Pattern; Pediatric Hospitals; Peer Review Grants; Peripheral; Philadelphia; Physicians; Pilot Projects; Preparation; Prevention; Protons; Publishing; Race; Radiation; Randomized Clinical Trials; Recovery; Regimen; Research; Research Activity; Research Personnel; Resistance; Resources; Risk; Risk Factors; Scientist; Secure; Serum; Skeletal Muscle; Somatomedins; Somatotropin; Stem cells; Structure; Survival Analysis; Survivors; Syndrome; Time; Tissues; Training; Transplantation; Transplantation Conditioning; United States National Institutes of Health; Weight-Bearing state; Whole-Body Irradiation; X-Ray Computed Tomography; base; bone; bone health; bone strength; cancer therapy; career; career development; clinical care; clinical epidemiology; clinically significant; cohort; experience; graft vs host disease; growth hormone deficiency; health related quality of life; hormone therapy; innovation; insight; irradiation; knowledge base; medical attention; mortality; multidisciplinary; muscle form; oncology; osteogenic; prevent; programs; research and development; sex; skeletal; skills; spine bone structure; stem; stem cell differentiation; substantia spongiosa; survivorship; therapeutic target; tibia; transcription factor; working group

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplantation (HSCT) is an established treatment for benign and malignant hemato- logic diseases in children. As mortality continues to decline, the focus of clinical care has turned to the identification and prevention of treatment-related complications in survivors of childhood HSCT. The overarching goal of this proposal is to identify therapeutic targets, and inform future clinical trials to treat these complications. The applicant recently published the first comprehensive studies of trabecular bone mineral density (BMD), cortical structure, and body composition in 55 long-term survivors of childhood HSCT. Despite completion of therapy years prior, these recipients had markedly increased whole body fat mass, decreased lean mass, and substantial deficits in trabecular BMD and cortical dimensions compared with >650 healthy reference participants. These findings herald significant risks for skeletal fragility and the metabolic syndrome, with substantil impact on health-related quality of life. Longitudinal studies are imperative to determine the onset and progression of these abnormalities, and to identify risk factors and therapeutic targets. This proposal will characterize changes in bone health, body composition, and fat distribution after childhood HSCT, and determine associations with insulin resistance, the metabolic syndrome, and bone deficits. The study has two primary components. The first component will examine early changes in skeletal parameters and body composition in a cohort of 60 newly transplanted pediatric HSCT recipients (short-term survivors) over two years. The second component will extend the applicant's recent study of long-term survivors to ex- amine changes in bone deficits, excess adiposity, and reduced muscle mass, and to identify risk factors for deterioration in these outcomes. The study will also examine fat distribution, insulin resistance, and the meta- bolic syndrome in both cohorts. A potential explanation for the bone deficits in HSCT survivors stems from the inverse relation between bone and fat formation within the bone marrow cavity, where hormones and transcription factors regulate mesenchyme stem cell (MSC) differentiation into osteoblasts or osteocytes. Since the original K07 application, the applicant was awarded a Foundation grant to evaluate marrow adipose tissue in HSCT survivors. The revised proposal now includes a highly innovative MR-spectroscopy measure of vertebral marrow adipose tissue and micro-MRI measures of bone microarchitecture in long-term HSCT survivors. These findings will provide significant insight into the fat-bone axis and its contribution to the bone and metabolic complications following HSCT. These data will be critical for the identification of potential interventions to target MSC differentiation, enhance bone formation, and reduce adiposity, and will form the basis of the applicant's future R01 proposals. The applicant is a dual certified pediatric endocrinologist and oncologist with advanced epidemiology training. Her research program is focused on bone, body composition, and metabolic abnormalities in survivors of childhood malignancies. In the interim since original submission of this proposal, the candidate completed a study on recovery of bone density and structure in children and adolescents after completion of therapy for acute lymphoblastic leukemia (manuscript under review), and a second study examining skeletal complications of growth hormone therapy in cancer survivors after radiation compared to children treated with growth hormone for idiopathic growth hormone deficiency (manuscript in preparation). The proposed research will provide the necessary experience in leading a complex longitudinal study in critically ill patients after HSCT, and will allow the candidate to pursue further trainin and support critical to her research and career development. The applicant will draw on outstanding resources, including the Children's Hospital of Philadelphia (CHOP) Cancer Center, the UPENN Clinical and Translational Research Center, Center for Clinical Epidemiology and Biostatistics, and the CHOP Cancer Survivorship Program. Accordingly, the candidate has assembled and will be guided by a renowned multidisciplinary Advisory Committee with expertise in epidemiology, biostatistics, oncology, endocrinology, and survivorship. The revised career development plan includes: (1) advanced epidemiology and biostatistics coursework selected to align with her career plan (e.g. longitudinal data analysis, clinical trial design, and survival analysis), (2) participation in the Childhood Cancer Survivor Study working groups for research activity, and (3) preparation of multiple peer-reviewed grants during the award to secure support for pilot and feasibility studies of potential interventions, while conducting research during the award period. The applicant's mentor is an NIH K24-funded senior investigator with expertise in bone health and body com- position in varied chronic diseases. The candidate's long-term career goal is to become a physician-scientist who conducts randomized clinical trials to treat the complications of childhood cancer therapy, and to provide expert clinical care for cancer survivors. This career development plan will build upon her knowledge base and epidemiology skills to complement the mentored research experience and will provide the foundation needed for her research focus in outcome and intervention trials in the field of Childhood Cancer Survivorship.

描述（由申请人提供）：造血干细胞移植（HSCT）是对儿童良性和恶性血液逻辑疾病的既定治疗方法。随着死亡率继续下降，临床护理的重点已转向识别和预防 儿童HSCT幸存者的治疗相关并发症。该提案的总体目标是确定治疗靶标，并告知未来的临床试验以治疗这些并发症。该申请人最近在55个儿童HSCT的长期幸存者中发表了第一个针对小梁骨矿物质密度（BMD），皮质结构和身体成分的全面研究。尽管在几年前完成了治疗，但这些受体显着增加了全身脂肪质量，瘦肉质量降低以及小梁BMD和皮质维度的大量缺陷，而> 650名健康的参考参与者。这些发现预示了骨骼脆弱性和代谢综合征的重大风险，对与健康相关的生活质量产生了重大影响。纵向研究必须确定这些异常的发作和进展，并确定危险因素和治疗靶标。该建议将表征儿童HSCT后骨骼健康，身体组成和脂肪分布的变化，并确定与胰岛素抵抗，代谢综合征和骨缺损的关联。该研究有两个主要组成部分。第一个组件将在两年内有60个新移植的小儿HSCT接受者（短期幸存者）组成的队列中的骨骼参数和身体成分的早期变化。第二个成分将扩大申请人对长期幸存者的最新研究，以表达骨缺损，肥胖过量和肌肉质量减少的胺变化，并确定这些结果中降低的危险因素。该研究还将检查两个队列中的脂肪分布，胰岛素抵抗和元体综合征。 HSCT幸存者中骨骼缺陷的潜在解释源于骨髓腔内骨与脂肪形成之间的反相关关系，激素和转录因子调节间质干细胞（MSC）分化成整骨细胞或成骨细胞。由于原始的K07应用程序， 申请人获得了基金会赠款，以评估HSCT幸存者中的骨髓脂肪组织。修订后的提案现在包括长期HSCT幸存者中椎骨脂肪组织的高度创新性MR谱镜测量和骨微体系结构的微MRI测量。这些发现将为脂肪骨轴及其它的脂肪骨轴提供重大见解 HSCT后对骨骼和代谢并发症的贡献。这些数据对于鉴定靶向MSC分化，增强骨骼形成并减少肥胖的潜在干预措施至关重要，并将构成申请人未来R01建议的基础。申请人是一名双重认证的小儿内分泌学家和高级流行病学培训的肿瘤学家。她的研究计划的重点是儿童恶性肿瘤幸存者的骨骼，身体组成和代谢异常。在此提案以来，在此期间，候选人完成了一项研究，完成了一项研究，在完成治疗急性淋巴细胞白血病治疗后，儿童和青少年的骨骼密度和结构的恢复研究（正在审查中的手稿），第二次研究，一项研究，研究了与儿童在辐射疗法后与癌症生长术相比，生长量的骨骼骨骼疗法的骨骼骨骼疗法的骨骼疗法的骨骼疗法，以辐射的生长量（IDI）的生长量（IDI）的生长。 准备）。拟议的研究将提供必要的经验，以领导HSCT后重症患者进行一项复杂的纵向研究，并使候选人能够进一步训练，并支持对她的研究和职业发展至关重要。申请人将利用杰出资源，包括费城儿童医院（CHOP）癌症中心，Upenn临床和转化研究中心，临床流行病学中心和 生物统计学和CHOP癌症生存计划。因此，候选人已经组建了，并将由著名的多学科咨询委员会指导，该委员会在流行病学，生物统计学，肿瘤学，内分泌学和生存方面具有专业知识。修订后的职业发展计划包括：（1）选择与她的职业计划保持一致的高级流行病学和生物统计学课程（例如，纵向数据分析，临床试验设计和 生存分析），（2）参与儿童癌症幸存者研究工作组的研究活动，以及（3）在奖励期间准备多个同行评审的赠款，以确保对试点的支持和对潜在干预措施的可行性研究，同时在奖励期间进行研究。申请人的导师是NIH K24资助的高级研究员，在各种慢性疾病中的骨骼健康和身体方面具有专业知识。候选人的长期职业目标是成为一名医师科学家，他进行随机临床试验以治疗儿童癌症治疗的并发症，并为癌症幸存者提供专家临床护理。这项职业发展计划将以她的知识库和流行病学技能为基础，以补充受过指导的研究经验，并将为她在儿童癌症生存领域的结果和干预试验中的研究重点提供基础。