Skeletal development and the hematopoietic niche

骨骼发育和造血生态位

基本信息

批准号：
8321902
负责人：
Olena Jacenko
金额：
$ 32.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8321902
关键词：
Adolescent Adult Affect Aging Blood Cells Bone Marrow Bone Marrow Transplantation Bone Surface Cartilage Cartilage Matrix Cell Differentiation process Cell Transplantation Cell physiology Cells Chondrocytes Collagen Data Defect Development Diagnosis Disease Environment Genetically Engineered Mouse Goals Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homing Image Immune Immune System Diseases Immune system Impairment Incidence Knockout Mice Label Laboratories Lymphocyte Lymphopoiesis Maintenance Malignant Neoplasms Marrow Mediating Microscopy Mus Neonatal Osteoblasts Pancytopenia Phenotype Photons Principal Investigator Process Proteins Regulation Skeletal Development Skeletal system Skeleton Stem cells System Tamoxifen Testing Therapeutic Time Tissues Transgenic Organisms Transplantation base bone cartilage matrix protein disease phenotype field study immune function in vivo innovation insight osteoprogenitor cell progenitor programs promoter public health relevance reconstitution skeletal skeletal tissue skeletogenesis stem stem cell biology stem cell niche substantia spongiosa two-photon

Adolescent Adult Affect Aging Blood Cells Bone Marrow Bone Marrow Transplantation Bone Surface Cartilage Cartilage Matrix Cell Differentiation process Cell Transplantation Cell physiology Cells Chondrocytes Collagen Data Defect Development Diagnosis Disease Environment Genetically Engineered Mouse Goals Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Homing Image Immune Immune System Diseases Immune system Impairment Incidence Knockout Mice Label Laboratories Lymphocyte Lymphopoiesis Maintenance Malignant Neoplasms Marrow Mediating Microscopy Mus Neonatal Osteoblasts Pancytopenia Phenotype Photons Principal Investigator Process Proteins Regulation Skeletal Development Skeletal system Skeleton Stem cells System Tamoxifen Testing Therapeutic Time Tissues Transgenic Organisms Transplantation base bone cartilage matrix protein disease phenotype field study immune function in vivo innovation insight osteoprogenitor cell progenitor programs promoter public health relevance reconstitution skeletal skeletal tissue skeletogenesis stem stem cell biology stem cell niche substantia spongiosa two-photon

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项目摘要

DESCRIPTION (provided by applicant): Certain immuno-osseous and hematopoietic disorders likely result from an impaired hematopoietic niche, which in turn may ensue from defective endochondral ossification (EO), where a cartilage skeletal blueprint is replaced by trabecular bone and marrow. This proposal will test our hypothesis that the EO- derived chondro-osseous junction (COJ), comprised of hypertrophic cartilage and trabecular bone, is a key hematopoietic niche within the marrow. This hypothesis stems from our transgenic (Tg) and null mice for collagen X, a matrix protein expressed in hypertrophic cartilage prior to EO. Mice with disrupted collagen X function display skeleto-hematopoietic defects including altered hypertrophic cartilage and trabecular bone in the COJ, marrow hypoplasia, diminished lymphopoiesis, and impaired immune function. We propose that these defects stem from an altered hematopoietic niche within the COJ, and that these mice provide an innovative system to identify the mechanistic basis for niche-mediated disorders. The goals of this proposal are to implicate a subset of COJ progenitors and collagen X as key regulators of the hematopoietic niche by: 1) Assessing by bone marrow transplantation if all hematopoietic defects in the collagen X mice could be attributed to niche impairment and whether homing of transplanted HSCs to the COJ niche could be visualized via two-photon microscopy; 2) Testing the ability of EO-progenitors from control and collagen X mice to reconstitute an ectopic COJ and HSC niche upon transplantation; and 3) Determining if EO-derived osteoprogenitors require collagen X for niche establishment and/or niche maintenance. PUBLIC HEALTH RELEVANCE: This proposal will test if the environment or "niche" in the marrow where blood cells form, is generated by a skeletal development process. We will use genetically engineered mice that have a niche defect to identify the skeletal components needed for proper formation and function of the blood cell niche. Data should yield insights into basic stem cell biology, as well as aid in diagnosis and treatment of niche-mediated diseases.

描述（由申请人提供）：某些免疫 - 骨和造血性疾病可能是由于造血壁she受损而导致的，而造血壁che则可能是由于内软骨骨化缺陷（EO）可能导致的，其中软骨骨骼蓝图被the骨骨骼和小tra骨骨骼和莫罗（Marrow）所代替。该提案将检验我们的假设，即由肥厚的软骨和小梁骨组成的EO衍生的软骨骨连接（COJ）是骨髓中的关键造血生态位。该假设源于我们用于胶原蛋白X的转基因（TG）和无效小鼠，胶原蛋白X是EO之前在肥厚性软骨中表达的基质蛋白。胶原蛋白X功能中断的小鼠显示骨架 - 毛to骨缺陷，包括改变肥厚的软骨和小梁骨的COJ，骨髓性发育不全，淋巴细胞减少和免疫功能受损。我们建议这些缺陷源于COJ内的造血生态位的改变，并且这些小鼠提供了一种创新的系统来识别小裂介导的疾病的机械基础。该提案的目标是将CoJ祖细胞和胶原X的子集牵连为造血壁iche的关键调节剂，1）通过：1）通过骨髓移植进行评估，如果胶原蛋白中的所有造血缺陷在胶原蛋白中的所有造血缺陷都可以通过niche的niche损害归因于niche the toture tote tosun to the therflant-thecon-thecoign-thecon-houthe the thecon-hsse nich nich nich nich nich nich nich nich nich nich nich nich nich nich nich niche显微镜； 2）在移植后测试来自对照和胶原蛋白X小鼠的EO - 培养基从对照和胶原蛋白X小鼠重建异位COJ和HSC壁ni的能力； 3）确定EO衍生的骨基因生成剂是否需要胶原蛋白X进行利基构建和/或利基维护。公共卫生相关性：该提案将测试由骨骼发育过程产生的血细胞形成的骨髓中的环境或“利基”。我们将使用具有生态位缺陷的基因工程小鼠来识别血细胞生态位适当形成和功能所需的骨骼成分。数据应带来对基本干细胞生物学的见解，并有助于诊断和治疗小裂介导的疾病。