Studies of HSC Engraftment at the Osteoblastic Niche for Inherited BM Failure

造骨细胞位 HSC 移植治疗遗传性 BM 失败的研究

• 批准号: 8676515
• 负责人: Timothy Steven Olson
• 金额: $ 13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676515
• 关键词: Advisory Committees; Affect; Affinity; Agreement; Animal Model; Applications Grants; Area; Automobile Driving; Award; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell Transplantation; Bone Marrow Transplantation; Cell Proliferation; Cell Survival; Cells; Cellular biology; Clinical; Clinical Investigator Award; Coculture Techniques; Committee Members; Data; Defect; Development; Diagnosis; Diamond; Disease; Doctor of Medicine; Doctor of Philosophy; Donor person; Dyskeratosis Congenita; Engraftment; Environment; Failure; Fanconi' s Anemia; Fellowship; Fostering; Functional disorder; Future; Future Generations; Goals; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune System Diseases; In Vitro; Indiana; Infusion procedures; Inherited; Insulin-Like Growth Factor I; International; Investigation; Label; Lead; Liver; Malignant Neoplasms; Mediating; Medicine; Megakaryocytes; Mentors; Mentorship; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Osteoblasts; Pancytopenia; Pathogenesis; Pathway interactions; Patient Care; Patients; Pediatric Hematology/Oncology; Pediatric Hospitals; Pediatrics; Pennsylvania; Philadelphia; Physicians; Platelet-Derived Growth Factor Receptor; Process; Production; Program Development; Receptor Signaling; Recombinants; Regimen; Research; Research Personnel; Residencies; Role; Scientist; Signal Pathway; Signal Transduction; Source; Stem cell transplant; Stem cells; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Thrombocytopenia; Thrombopoietin; Time; Tissues; Training; Training Programs; Transgenic Mice; Transplantation; Universities; Whole-Body Irradiation; base; career; career development; conditioning; experience; graft failure; improved; in vivo; migration; mouse model; novel therapeutics; platelet-derived growth factor BB; professor; programs; public health relevance; research study; response; skills; stem cell niche; success; therapy design; Advisory Committees; Affect; Affinity; Agreement; Animal Model; Applications Grants; Area; Automobile Driving; Award; Biology; Blood; Blood Cells; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell Transplantation; Bone Marrow Transplantation; Cell Proliferation; Cell Survival; Cells; Cellular biology; Clinical; Clinical Investigator Award; Coculture Techniques; Committee Members; Data; Defect; Development; Diagnosis; Diamond; Disease; Doctor of Medicine; Doctor of Philosophy; Donor person; Dyskeratosis Congenita; Engraftment; Environment; Failure; Fanconi' s Anemia; Fellowship; Fostering; Functional disorder; Future; Future Generations; Goals; Hematology; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune System Diseases; In Vitro; Indiana; Infusion procedures; Inherited; Insulin-Like Growth Factor I; International; Investigation; Label; Lead; Liver; Malignant Neoplasms; Mediating; Medicine; Megakaryocytes; Mentors; Mentorship; Mesenchymal; Modeling; Molecular; Morbidity - disease rate; Mus; Osteoblasts; Pancytopenia; Pathogenesis; Pathway interactions; Patient Care; Patients; Pediatric Hematology/Oncology; Pediatric Hospitals; Pediatrics; Pennsylvania; Philadelphia; Physicians; Platelet-Derived Growth Factor Receptor; Process; Production; Program Development; Receptor Signaling; Recombinants; Regimen; Research; Research Personnel; Residencies; Role; Scientist; Signal Pathway; Signal Transduction; Source; Stem cell transplant; Stem cells; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Studies; Thrombocytopenia; Thrombopoietin; Time; Tissues; Training; Training Programs; Transgenic Mice; Transplantation; Universities; Whole-Body Irradiation; base; career; career development; conditioning; experience; graft failure; improved; in vivo; migration; mouse model; novel therapeutics; platelet-derived growth factor BB; professor; programs; public health relevance; research study; response; skills; stem cell niche; success; therapy design

DESCRIPTION (provided by applicant): This proposal describes a 4 year training program for the development of my academic career in Pediatric Hematology, Oncology, and Stem Cell Transplantation. I have completed formal residency training in General Pediatrics and subspecialty fellowship training in Pediatric Hematology and Oncology at The Children's Hospital of Philadelphia (CHOP). I now seek to expand my scientific skills to enable my transition to becoming a successful independent investigator. My research program will promote discoveries in stem cell niche biology, mechanisms of donor stem cell engraftment following transplantation, and pathogenic mechanisms of graft failure in models of inherited bone marrow failure syndromes. Dr. Monica Bessler, M.D., Ph.D. and Dr. Edwin Horwitz, M.D., Ph.D., will mentor my scientific development. Dr. Bessler, Director of the Comprehensive Bone Marrow Failure Center at CHOP and the University of Pennsylvania (UPENN), is an international leader in research dedicated to the diagnosis and pathogenesis of bone marrow failure conditions, and has successfully mentored numerous trainees who have become leaders in academic medicine. Dr. Horwitz, Associate Professor of Pediatrics at CHOP and UPENN, is an international leader in the fields of bone marrow mesenchymal cell biology and cellular therapy, and has a growing record of fostering trainee career development. My mentorship team provides an ideal combined expertise and experience to facilitate my successful completion of this research program. I have also organized a Scientific Advisory Committee of highly regarded investigators consisting of Drs. Mortimer Poncz, M.D., Stephan Grupp, M.D. Ph.D., and Philip Mason, Ph.D., whose combined expertise in megakaryocyte biology, cellular therapy research, bone marrow failure models, and career development will provide invaluable contributions to my future success. Additionally, I have formed collaborative agreements with Dr. D. Wade Clapp from the University of Indiana, and Dr. Johanna Rommens from the University of Toronto, to provide me with specific mouse models of bone marrow failure critical for the success of these studies. The research builds upon my previous investigations demonstrating that reorganization and expansion of the osteoblastic hematopoietic stem cell (HSC) niche in response to transplant myeloablative conditioning regimens are essential for efficient HSC engraftment. Our proposed experiments will utilize transgenic mouse models and therapeutic interventions designed to disrupt or enhance this niche reorganization, and will identify whether these alterations influence the capacity of the niche to engraft donor HSC. The specific aims include: 1) Identifying synergistic and essential mechanisms by which PDGF-BB, IGF-1, and megakaryocyte migration to the osteoblastic niche influence niche expansion and HSC engraftment, 2) Investigating whether models of inherited bone marrow failure demonstrate intrinsic deficits in niche function resulting in poor donor HSC engraftment, and 3) Determining whether PDGF-BB administration or megakaryocyte infusion can enhance niche expansion and niche capacity to engraft donor HSC. Our completion of these proposed studies will have profound translational implications in 1) discovering the cellular and molecular mechanisms that drive successful stem cell engraftment at the niche, 2) determining how niche dysfunction may lead to graft failure, and 3) identifying rationally targeted therapies to enhance successful donor engraftment rates following clinical stem cell transplantation. My prior research efforts were focused on the hematopoietic stem cell niche. Training through this K08 award will expand both my scientific training to discover roles of the hematopoietic niche in bone marrow failure syndromes, while at the same time facilitating my development of clinical career skills in the care of patients affected by thes disorders. These two new directions will involve mentoring and training in the scientific areas related to inherited and acquired bone marrow failure, and will be the primary focus of my interactions with Dr. Bessler as senior mentor. The numerous interdisciplinary centers, collaborative investigator affinity groups, and unique didactic training opportunities at CHOP and UPENN provide an exceptional scientific environment for the training of physician-scientists. I plan to take full advantage of the diverse intellectual areas of expertise and academic experiences of my outstanding mentors, advisory committee members, and collaborators to successfully develop my unique and independent program of scientific investigation. Given the exceptional opportunities and training afforded by this prestigious K08 program, I will devote my career to making high impact scientific contributions to the field of hematology and to training future generations of physician-scientists.

描述（由申请人提供）：该提案描述了一项为期4年的培训计划，以发展我在儿科血液学，肿瘤学和干细胞移植方面的学术生涯。我已经在费城儿童医院（CHOP）完成了一般儿科和专科奖学金培训的正规居住培训。现在，我寻求扩大我的科学技能，以使自己的过渡成为成功的独立研究者。我的研究计划将促进干细胞生物学生物学的发现，移植后供体干细胞植入的机制以及遗传性骨髓衰竭综合征模型中移植物衰竭的致病机制。 Monica Bessler博士，医学博士，博士医学博士Edwin Horwitz博士将指导我的科学发展。贝斯勒（Bessler）博士是CHOP综合骨髓衰竭中心和宾夕法尼亚大学（UPENN）的主任，是致力于骨髓衰竭条件诊断和发病机理的研究领域的国际领导者，并成功地指导了许多已成为学术医学领导者的学员。 Chop and Upenn儿科副教授Horwitz博士是骨髓间充质细胞生物学和细胞疗法领域的国际领导者，并且在培养学员职业发展方面越来越多地记录。我的指导团队提供了理想的综合专业知识和经验，以促进我成功完成该研究计划。我还组织了一个由DRS组成的备受推崇的研究人员的科学咨询委员会。 Mortimer Poncz，M.D。，Stephan Grupp，M.D。博士学位和Philip Mason，Ph.D.，其在Megakaryocyte生物学，细胞疗法研究，骨髓失败模型和职业发展方面的综合专业知识将为我未来的成功提供宝贵的贡献。此外，我已经与印第安纳大学的D. Wade Clapp博士和多伦多大学的Johanna Rommens博士达成了合作协议，为我提供了对这些研究成功至关重要的骨髓失败的特定鼠标模型。这项研究基于我以前的研究，表明成骨细胞造血干细胞（HSC）like的重组和扩展，响应于移植的髓质损伤条件方案对于有效的HSC摄取至关重要。我们提出的实验将利用旨在破坏或增强这种利基重组的转基因小鼠模型和治疗性干预措施，并将确定这些改变是否影响 利基市场植入供体HSC的容量。具体目的包括：1）识别PDGF-BB，IGF-1和巨核细胞迁移到成骨细胞的扩张和HSC植入的迁移的协同和基本机制。给药或巨核细胞输注可以增强利基扩展和植入供体HSC的利基市场能力。我们完成这些拟议的研究将在1）发现在细分市场上成功的细胞和分子机制具有深远的翻译意义，2）确定壁nike功能障碍如何导致移植失败，并且3）3）识别合理靶向的疗法以增强临时干细胞置换后成功的供体雕刻剂。我先前的研究工作集中于造血干细胞生态位。通过这一K08奖的培训将扩大我的科学培训，以发现造血生态位在骨髓衰竭综合征中的作用，同时促进我在受到这种疾病影响的患者护理中临床职业技能的发展。这两个新的方向将涉及与继承和获得的骨髓失败有关的科学领域的指导和培训，这将是我与贝斯勒博士担任高级导师的互动的主要重点。众多的跨学科中心，合作调查员亲和力小组以及在Chop和Upenn的独特教学培训机会为培训医师科学家提供了卓越的科学环境。我计划充分利用我杰出的导师，咨询委员会成员和合作者的专业知识和学术经验的各种知识领域，以成功地制定我独特而独立的科学研究计划。鉴于这个享有声望的K08计划提供了出色的机会和培训，我将致力于为血液学领域和培训子孙后代的医师科学家做出高影响力的科学贡献。