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

基本信息

批准号：
9266372
负责人：
Sogol Mostoufi-Moab
金额：
$ 16.49万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-04 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9266372
关键词：
Acute Lymphocytic Leukemia Adipose tissue Adolescent Advisory Committees Age Amination Amines Award Benign Biometry Body Composition Body fat Bone Density Bone Marrow Bone Marrow Transplantation Bone structure Cancer Center Cancer Survivor Cancer Survivorship Cell Culture Techniques Cell Differentiation process 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 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 Impairment Insulin Resistance Intervention Intervention Trial Long-Term Survivors Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant - descriptor Malignant Childhood Neoplasm Manuscripts Marrow Measures Mentors Mesenchymal Stem Cells 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 Resources Risk Risk Factors Scientist Secure Serum Skeletal Muscle Somatomedins Somatotropin Stem cells Structure Survival Analysis Survivors Thinness Training Transplantation Transplantation Conditioning United States National Institutes of Health Weight-Bearing state Whole-Body Irradiation X-Ray Computed Tomography bone bone health bone strength cancer therapy career career development clinical care clinical epidemiology clinically significant cohort cortical bone 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 reduced muscle mass research and development sex skeletal skills spine bone structure stem stem cell differentiation substantia spongiosa survivorship therapeutic target tibia transcription factor working group

项目摘要

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 metabolic 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）是治疗儿童良性和恶性血液疾病的既定疗法。随着死亡率持续下降，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点，并为未来治疗这些并发症的临床试验提供信息。申请人最近发表了第一份针对 55 名儿童 HSCT 长期幸存者的小梁骨矿物质密度 (BMD)、皮质结构和身体成分的综合研究。尽管多年前就完成了治疗，但与超过 650 名健康参考参与者相比，这些接受者的全身脂肪量显着增加，瘦肉量减少，小梁 BMD 和皮质尺寸显着缺陷。这些发现预示着骨骼脆弱和代谢综合征的重大风险，对健康相关的生活质量产生重大影响。必须进行纵向研究来确定这些异常的发生和进展，并确定危险因素和治疗目标。该提案将描述儿童 HSCT 后骨骼健康、身体成分和脂肪分布的变化，并确定与胰岛素抵抗、代谢综合征和骨骼缺陷的关系。该研究有两个主要组成部分。第一个部分将检查两年内 60 名新移植儿科 HSCT 受者（短期幸存者）的骨骼参数和身体成分的早期变化。第二部分将扩展申请人最近对长期幸存者的研究，以检查骨缺损、过度肥胖和肌肉质量减少的变化，并确定这些结果恶化的风险因素。该研究还将检查两个队列中的脂肪分布、胰岛素抵抗和代谢综合征。造血干细胞移植幸存者骨缺陷的一个可能解释源于骨髓腔内骨和脂肪形成之间的反比关系，其中激素和转录因子调节间充质干细胞（MSC）分化为成骨细胞或骨细胞。自从最初的K07申请以来，申请人获得了基金会拨款，用于评估 HSCT 幸存者的骨髓脂肪组织。修订后的提案现在包括对椎骨骨髓脂肪组织进行高度创新的 MR 光谱测量，以及对长期 HSCT 幸存者的骨微结构进行微型 MRI 测量。这些发现将为脂肪骨轴及其结构提供重要的见解。 HSCT 后骨和代谢并发症的贡献。这些数据对于确定针对 MSC 分化、增强骨形成和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 提案的基础。申请人是经过高级流行病学培训的双认证儿科内分泌学家和肿瘤学家。她的研究项目主要关注儿童恶性肿瘤幸存者的骨骼、身体成分和代谢异常。自最初提交该提案以来，候选人完成了一项关于儿童和青少年在完成急性淋巴细胞白血病治疗后骨密度和结构恢复的研究（手稿正在审查中），以及第二项研究检查生长激素的骨骼并发症放疗后癌症幸存者的治疗与因特发性生长激素缺乏症而接受生长激素治疗的儿童进行比较（手稿正在准备中）。拟议的研究将为 HSCT 后危重患者进行复杂的纵向研究提供必要的经验，并使候选人能够接受对其研究和职业发展至关重要的进一步培训和支持。申请人将利用优秀资源，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，候选人已经组建了一个著名的多学科咨询委员会，并将接受该委员会的指导，该委员会拥有流行病学、生物统计学、肿瘤学、内分泌学和生存学方面的专业知识。修订后的职业发展计划包括：（1）选择与她的职业计划相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）在颁奖期间准备多项同行评审赠款，以确保对潜在干预措施的试点和可行性研究的支持，同时在颁奖期间开展研究奖励期限。申请人的导师是一位 NIH K24 资助的高级研究员，在各种慢性疾病的骨骼健康和身体成分方面拥有专业知识。候选人的长期职业目标是成为一名医师科学家，进行随机临床试验来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。该职业发展计划将建立在她的知识基础和流行病学技能的基础上，以补充指导的研究经验，并将为她在儿童癌症生存领域的结果和干预试验方面的研究重点提供所需的基础。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Bone morbidity in childhood leukemia: epidemiology, mechanisms, diagnosis, and treatment.

DOI：
10.1007/s11914-014-0222-3
发表时间：
2014-09
期刊：
CURRENT OSTEOPOROSIS REPORTS
影响因子：
4.3
作者：
Mostoufi-Moab, Sogol;Halton, Jacqueline
通讯作者：
Halton, Jacqueline

Sarcopenia and preserved bone mineral density in paediatric survivors of high-risk neuroblastoma with growth failure.

DOI：
10.1002/jcsm.12734
发表时间：
2021-08
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
0
作者：
Guo M;Zemel BS;Hawkes CP;Long J;Kelly A;Leonard MB;Jaramillo D;Mostoufi-Moab S
通讯作者：
Mostoufi-Moab S

Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after cis-Retinoic Acid Therapy in Medulloblastoma: A Case Report.

髓母细胞瘤顺式视黄酸治疗后下肢骨骺过早闭合导致身材矮小：病例报告。