Hematopoietic Stem Cell Transplantation in Osteogenesis Imperfecta

造血干细胞移植治疗成骨不全症

• 批准号: 8046393
• 负责人: Meenal Mehrotra
• 金额: $ 6.9万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8046393
• 关键词: A Mouse; Adipocytes; Adult; Affect; Area; Asses; Biology; Blood Cells; Bone Diseases; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; Bone Matrix; Bone Resorption; Bone remodeling; CD34 gene; COL1A2 gene; CXCR4 gene; Cardiovascular system; Cartilage; Cells; Characteristics; Child; Chondrocytes; Clinical Trials; Collaborations; Collagen; Collagen Diseases; Collagen Type I; Connective Tissue; Core Facility; Data; Defect; Deformity; Dentinogenesis Imperfecta; Diagnosis; Diaphyses; Disease; Doctor of Philosophy; Dysplasia; Early treatment; Experimental Designs; Fatty acid glycerol esters; Fibroblasts; Flare; Fracture; Future; Genes; Goals; Granulocyte Colony-Stimulating Factor; Growth; Healed; Hematopoietic; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hereditary Disease; Histocompatibility Testing; Hormones; Human; In Vitro; Inherited; Investigation; Knowledge; Label; Laboratories; Lead; Manuscripts; Marrow; Mentored Research Scientist Development Award; Mentors; Mesenchymal; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Methods; Minerals; Modeling; Mus; Mutation; Myofibroblast; Neonatal; Newborn Infant; Normal Cell; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteogenesis Imperfecta; Osteopenia; Parathyroid gland; Pathology; Patients; Population; Postdoctoral Fellow; Preparation; Production; Puberty; Publishing; Reporting; Research; Research Personnel; Role; Scientist; Sclera; Severities; Shapes; Side; Site; Source; Staging; Stem cells; Stromal Cells; Structural Protein; Structure; Symptoms; Techniques; Testing; Therapeutic; Tissues; Training; Transplantation; Trauma; United States National Institutes of Health; Variant; base; bone; bone strength; bone turnover; career; career development; clinical effect; enhanced green fluorescent protein; healing; hearing impairment; improved; in vivo; interest; mast cell; mouse model; novel; osteoprogenitor cell; preclinical study; prevent; progenitor; programs; reconstitution; repaired; research study; skeletal; skeletal disorder therapy; soft tissue; stem cell biology; theories

DESCRIPTION (provided by applicant): I realized my interest in bone biology during my Ph.D. and Post Doctoral years. Since joining my Mentor's lab, I have gained considerable knowledge in stem cell biology. Thus, I have decided to combine my background in bone biology with my current studies of stem cells to investigate the hematopoietic stem cells (HSCs) as a potential therapy for bone disorders. Long-term, the proposed studies will help me to distinguish myself as an independent investigator and develop my own area of research. Even though I am proficient in execution of techniques, I am still lacking in planning and critical assessment of experiments and in preparation of manuscripts. Further training under my Mentor and Co-Mentor will solidify my knowledge in stem cell biology, and help me to achieve a greater understanding and mastery of experimental design and grantsmanship, a critical step before I can realize more independence as an academic scientist. In addition to my Mentor and Co-Mentor, I have established collaborations with other senior investigators with expertise specifically relevant to the proposed studies. I also have full Departmental support for this application including career development programs and use of core facilities. Support from the Mentored Research Scientist Development Award will allow me to focus on this continued training over the next few critical years to further both my own career development and the investigation of the aims of this proposal. I have a strong desire to develop a successful career and carve a niche for myself in the area of basic and translational bone research. The receipt of the NIH support at this stage of my training is critical to my realization of this goal. This application will focus on Osteogensis Imperfecta (OI) and the role of HSCs as a potential therapy for this disease. OI or "brittle bone disease", a genetic disorder resulting from the abnormal amount and/or structure of Type I collagen, is the most common hereditary bone disease. It is characterized by moderately to extremely fragile bones which may fracture upon little or no trauma, skeletal deformities, osteopenia and short stature. Presently there is no cure for OI. Ideally, therapy for OI should be directed towards improving bone strength by improving the production and integrity of the secreted collagen. Preclinical studies have demonstrated that bone marrow contains cells that can engraft and become competent osteoblasts after transplantation. Clinical trials using bone marrow stem cells in a small number of children with severe forms of OI have shown promising results with increased growth velocity, total body mineral content and fewer fractures. Although bone marrow transplantation shows potential, there is a controversy regarding the cell involved. Current dogma states that bone marrow contains two types of stem cells, HSCs and mesenchymal stem cells (MSCs), and that their repertoire of reconstituting potentials are distinct and separate from each other; i.e. HSCs produce blood cells and few other cells like mast cells and osteoclasts, while MSCs generate a number of mesenchymal cells including fibroblasts, adipocytes, chondrocytes and osteoblasts. Recently, studies have begun to question the distinction between the potentials of HSCs and MSCs in generating osteoblasts and osteocytes. My Mentor has developed a novel transplantation model in which the bone marrow of lethally irradiated recipient mice is reconstituted by a clonal population of cells derived from a single EGFP+ HSC. Studies using this model have demonstrated that many types of tissue fibroblasts/ myofibroblasts as well as adipocytes are derived from HSCs, suggesting an HSC contribution to multiple mesenchymal tissues. Preliminary in vivo data also supports an HSC origin for osteoblasts and osteocytes. Therefore, we hypothesize that the primary defect in OI is in the HSC. We propose to test this hypothesis using single HSC transplantation in combination with a mouse model of OI, the oim/oim mouse. Based on our hypothesis, HSC transplantation should lead to replacement of affected osteoblasts with normal cells, in turn correcting collagen defects in bone and ameliorating and/or preventing OI pathologies. Long term, these findings have the potential to identify HSC transplantation, and not the transplantation of MSCs or progenitor cells, as the therapy of choice for this collagen disorder.

描述（由申请人提供）：我在博士期间意识到我对骨生物学的兴趣。博士后岁月自从加入导师的实验室，我在干细胞生物学方面获得了相当多的知识。因此，我决定将我的骨生物学背景与我目前对干细胞的研究相结合，研究造血干细胞（HSCs）作为骨疾病的潜在治疗方法。从长远来看，这些研究将帮助我成为一名独立的研究者，并发展自己的研究领域。尽管我精通技术的执行，但我仍然缺乏对实验的计划和批判性评估以及手稿的准备。在我的导师和合作导师的进一步培训将巩固我在干细胞生物学方面的知识，并帮助我更好地理解和掌握实验设计和实验，这是我作为学术科学家实现更多独立性的关键一步。除了我的导师和合作导师外，我还与其他高级研究者建立了合作关系，这些研究者具有与拟定研究特别相关的专业知识。我也有充分的部门支持这个应用程序，包括职业发展计划和使用的核心设施。来自指导研究科学家发展奖的支持将使我能够在接下来的几年里专注于这种持续的培训，以促进我自己的职业发展和对本提案目标的调查。我有一个强烈的愿望，发展一个成功的职业生涯，并为自己在基础和转化骨研究领域的利基。在我培训的这个阶段，接受NIH的支持对我实现这一目标至关重要。该申请将重点关注成骨不全（OI）和HSC作为这种疾病的潜在治疗方法的作用。OI或“脆骨病”，一种由I型胶原蛋白的异常量和/或结构引起的遗传性疾病，是最常见的遗传性骨病。其特征在于中度至极度脆弱的骨骼，在很少或没有创伤的情况下可能骨折，骨骼畸形，骨质减少和身材矮小。目前还没有治愈OI的方法。理想情况下，OI的治疗应该通过改善分泌的胶原蛋白的产生和完整性来改善骨强度。临床前研究表明，骨髓中含有可以移植并在移植后成为成骨细胞的细胞。在少数严重OI儿童中使用骨髓干细胞的临床试验显示出有希望的结果，生长速度增加，全身矿物质含量增加，骨折减少。虽然骨髓移植显示出潜力，但关于所涉及的细胞存在争议。目前的理论认为，骨髓含有两种类型的干细胞，HSC和间充质干细胞（MSC），并且它们的重建潜能库是不同的并且彼此分离;即HSC产生血细胞和很少的其他细胞，如肥大细胞和破骨细胞，而MSC产生许多间充质细胞，包括成纤维细胞、脂肪细胞、软骨细胞和成骨细胞。最近，研究已经开始质疑HSC和MSC在生成成骨细胞和骨细胞方面的潜力之间的区别。My Mentor开发了一种新的移植模型，其中致死辐射受体小鼠的骨髓由来自单个EGFP+ HSC的细胞克隆群重建。使用该模型的研究已经证明，许多类型的组织成纤维细胞/肌成纤维细胞以及脂肪细胞来源于HSC，表明HSC对多种间充质组织的贡献。初步的体内数据也支持成骨细胞和骨细胞的HSC起源。因此，我们假设OI的主要缺陷在HSC中。我们建议使用单一HSC移植结合OI小鼠模型（oim/oim小鼠）来检验这一假设。基于我们的假设，HSC移植应该导致用正常细胞替换受影响的成骨细胞，从而纠正骨中的胶原缺陷并改善和/或预防OI病理。从长远来看，这些发现有可能确定HSC移植，而不是MSC或祖细胞的移植，作为这种胶原蛋白疾病的治疗选择。