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Discoidin Domain Receptor 2, β1 Integrins and ECM Control of Bone Formation

Discoidin 结构域受体 2、β1 整合素和 ECM 对骨形成的控制

基本信息

批准号：
10117775
负责人：
Renny Theodore Franceschi
金额：
$ 47.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-12 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117775
关键词：
Affect Agonist Anabolic Agents Area Basic Science Binding Bone Diseases Bone Growth Bone Regeneration Bone Surface Cartilage Cell Differentiation process Cell Lineage Cell physiology Cells Cephalic Chondrocytes Collagen Collagen Receptors Craniofacial Abnormalities Data Development Diabetes Mellitus Disease Dysplasia Endosteum Epiphysial cartilage Extracellular Matrix Face Fibrillar Collagen Gene Expression Profile Genes Growth Growth and Development function Health Human Immunofluorescence Immunologic In Vitro Integrins Joint structure of suture of skull Knock-out LacZ Genes Limb structure Mature Bone Mission Molecular Profiling Mus Mutation Osteoblasts Osteogenesis Osteoporosis Pathway interactions Pattern Peptides Periosteum Phenotype Population Public Health Rest Role Route Shapes Signal Pathway Signal Transduction Site Skeletal Development Skeleton Structure of fontanel of skull Testing Time bone bone cell bone mass conditional knockout cortical bone craniofacial craniofacial development cranium discoidin domain receptor 2 experimental study genetic approach improved in vivo insight long bone novel osteoblast differentiation osteogenic osteoprogenitor cell public health relevance repaired single-cell RNA sequencing skeletal skeletal abnormality skeletal regeneration skeletal stem cell skull abnormality skull base substantia spongiosa suture fusion synergism

项目摘要

Discoidin domain receptor 2 (DDR2) is a non-integrin collagen receptor having important but poorly understood skeletal functions. Inactivating mutations in DDR2 cause spondylo-meta-epiphyseal dysplasia (SMED-short limb type), a human disorder with severe craniofacial and skeletal abnormalities. Ddr2-deficient mice have a similar phenotype including abnormal skull shape, delayed suture fusion and defective cartilage growth/orientation in synchondroses at the base of the skull, shortened long bone growth plates and reduced trabecular and cortical bone mass. Preliminary studies where Ddr2 was selectively inactivated in skeletal progenitors indicate distinct functions in cells of the bone lineage. Studies will test the following hypothesis: DDR2 is an important regulator of bone formation that functions in bone lineage cells to sense the collagenous ECM niche and thereby stimulate SPC lineage commitment and differentiation; on activation by fibrillar collagens, DDR2 synergistically interacts with β1 integrins to stimulate osteoblast differentiation. Aims are: 1. Establish the distribution, fates and gene expression profile of Ddr2-positive cells during craniofacial and skeletal development. Hypothesis: During development, Ddr2 is expressed in SPCs as well as more mature bone cells. Studies will: a) establish the time course and pattern of Ddr2 expression during skeletal development, b) define the lineage of Ddr2-expressing cells, c) Define the molecular signature of Ddr2-expressing cells and their progeny using single-cell RNAseq. 2. Define the cellular sites of action of DDR2 in the craniofacial and appendicular skeleton. Hypothesis: Ddr2 functions in both SPCs and committed chondrogenic and osteogenic cells to stimulate bone formation. It is not known which skeletal cells require DDR2 for normal function; skeletal SCs, differentiated cells or both. a) To define cellular functions of DDR2, a targeted deletion approach will be used to inactivate Ddr2 in Gli+ craniofacial/skeletal progenitors, chondrocytes and osteoblasts. b) To determine if Ddr2 controls the differentiation of SPCs, the effect of Ddr2 deficiency on the lineage of Gli1+ SPCs will be examined. 3. Examine the mechanistic basis for interactions between DDR2 and collagen-binding β1 integrins. Hypothesis: DDR2 and β1 integrins synergistically interact to stimulate cellular activity. Collagen-binding β1 integrins and DDR2 synergistically interact. The mechanistic basis for this synergy will be established using in vitro and in vivo approaches as follows: a. Examine interactions between DDR2 and integrin signaling during osteoblast differentiation. b. Use a genetic approach to detect Ddr2 and β1 integrin interactions in vivo. Proposed studies will elucidate the skeletal functions of DDR2 and its interactions with β1 integrins. This is a highly significant but understudied area with important implications for understanding the role of cell- collagen interactions in bone diseases including SMED, osteoporosis and diabetes. In addition, bone-targeted DDR2 agonists if developed could be a new class of bone anabolic agents.

盘状结构域受体2（DDR2）是一种非整联蛋白胶原蛋白受体，具有重要但知之甚少的功能。骨骼功能DDR2的失活突变会导致脊椎间骨骺发育不良（SMED-短肢体型），一种具有严重颅面和骨骼异常的人类疾病。DDR2缺陷小鼠具有相似的表型包括颅骨形状异常、缝线融合延迟和软骨缺损生长/方向在软骨结合在颅底，缩短长骨生长板和减少骨小梁和皮质骨质量。Ddr2在骨骼肌中选择性失活的初步研究祖细胞在骨谱系细胞中显示不同的功能。研究将检验以下假设： DDR2是骨形成的重要调节因子，其在骨谱系细胞中起作用以感知胶原ECM小生境并由此刺激SPC谱系定型和分化;在被纤维状胶原激活时，DDR2 与β1整联蛋白协同相互作用以刺激成骨细胞分化。目标是： 1.建立Ddr2阳性细胞在颅面和颞下颌关节中的分布、命运和基因表达谱。骨骼发育假设：在发育过程中，Ddr2在SPC以及更成熟的骨细胞中表达。研究将：a）建立骨骼发育过程中Ddr 2表达的时间过程和模式，B）定义 c）定义表达Ddr2的细胞的分子特征和它们的分子标记。使用单细胞RNAseq. 2.定义DDR2在颅面和骨外骨骼中的细胞作用位点。假设：Ddr2 在SPCs和定向的软骨细胞和成骨细胞中起作用以刺激骨形成。目前还不知道哪些骨骼细胞需要DDR2来实现正常功能;骨骼SC、分化的细胞或两者。（a）界定 DDR2的细胞功能，将使用靶向缺失方法在Gli+中缺失DDR2 颅面/骨骼祖细胞、软骨细胞和成骨细胞。B）为了确定Ddr2是否控制为了观察SPC的分化，将检查Ddr2缺乏对Gli 1 + SPC谱系的影响。 3.检查DDR2和胶原结合β1整合素之间相互作用的机制基础。假设：DDR2和β1整联蛋白协同相互作用以刺激细胞活性。胶原结合β1整合素和DDR2协同作用。这种协同作用的机制基础将使用体外和体内方法如下：a.研究成骨细胞生长过程中DDR2和整合素信号之间的相互作用分化B.使用遗传学方法检测体内Ddr 2和β1整合素相互作用。拟议的研究将阐明DDR2的骨骼功能及其与β1整合素的相互作用。这是这是一个非常重要但研究不足的领域，对于理解细胞的作用具有重要意义- 骨疾病中的胶原相互作用，包括SMED、骨质疏松症和糖尿病。此外，骨靶向 DDR2激动剂，如果开发可能是一类新的骨合成代谢剂。