"Establishing Pathways for Endothelial Support of Bone Formation with SLIT3"

“利用 SLIT3 建立内皮支持骨形成的途径”

• 批准号: 10571692
• 负责人: Matthew Blake Greenblatt
• 金额: $ 37.29万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571692
• 关键词: Address; Adopted; Anatomy; Angiogenic Factor; Area; Automobile Driving; Blood; Blood Vessels; Categories; Cell Communication; Cell Lineage; Cells; Clinical; Coculture Techniques; Complement; Coupling; Discontinuous Capillary; Drug Targeting; Endothelial Cells; Endothelium; Foundations; Growth Factor; LEPR gene; Location; Mediating; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Metabolic Bone Diseases; Modeling; Morphology; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Pathway interactions; Phenotype; Physiological; Play; Population; Postmenopausal Osteoporosis; Production; Regulation; Reporting; Role; Shapes; Signal Induction; Signal Transduction; Source; Stimulus; Structure; Supporting Cell; Testing; Therapeutic; Transplantation; Vascular Endothelial Cell; Vascular Endothelium; Work; angiogenesis; arteriole; bone; bone fracture repair; bone growth factor; bone loss; cell type; cellular targeting; drug development; mouse model; new growth; novel; novel strategies; prevent; progenitor; receptor; response; skeletal; skeletal disorder; skeletal stem cell; stem cell population; stem cells; therapeutic candidate; tool

Project Summary/Abstract Recent work establishes that skeletal blood vessels are not just mere channels for blood, but instead play an active role in supporting bone formation. However, it is unknown which types of blood vessels provide this support, how these blood vessels alter the production of bone forming cells from their stem cell progenitors, or how this coupling between blood vessels and bone forming cells is tied to the overall physiologic demand for bone formation. Progress in this area has been impeded by most of the growth factors for blood vessels in bone also having direct effects on bone forming cells, preventing their use to study interactions between blood vessels and bone forming cells. We have recently identified a new growth factor for skeletal blood vessels, SLIT3. SLIT3 is produced by bone forming cells and increases bone formation not by targeting bone forming cells themselves, but instead by promoting outgrowth of blood vessels that in turn support bone formation. Thus, SLIT3 presents an attractive tool to study which blood vessels in bone influence bone formation and how these blood vessels shape the production of bone forming cells. Furthermore, recent advances in understanding skeletal stem cells from ourselves and others identify that bone contains multiple populations of stem cells giving rise to bone forming cells, with each of these stem cells having a different anatomic location and function. It is unlikely that a single type of blood vessel is able to support all of these different of skeletal stem cell populations, and we accordingly hypothesize that different types of skeletal blood vessels each support different types of skeletal stem cells. Here, SLIT3 to both address this hypothesis and establish fundamental paradigms for how endothelial cells support bone formation. In Aim 1, we will study how SLIT3-mediated outgrowth of skeletal blood vessels is driven by signals known to promote bone formation, determining if this SLIT3-driven blood vessel outgrowth is needed for the bone formation response to these signals and also which subsets of bone forming cells are the key producers of SLIT3 needed for these responses. In Aim 2, we will determine which specific bone forming cells are supported by each blood vessel type induced by SLIT3. In Aim 3, we will determine how SLIT3-induced blood vessels shape the differentiation of bone forming cells. Overall, this work will provide a foundation for the development of drugs targeting skeletal blood vessels as a new approach to treat osteoporosis and other skeletal disorders. !

项目摘要/摘要 最近的工作确定，骨骼血管不仅仅是血液的通道，而且是 而是在支撑骨形成中发挥积极作用。但是，未知是哪种类型的 血管提供了这种支持，这些血管如何改变骨骼的产生 由干细胞祖细胞形成细胞，或者如何在血管和 骨形成细胞与骨形成的总体生理需求有关。进步 大多数骨血管的大多数生长因子都阻碍了区域 直接对骨形成细胞的影响，阻止它们用于研究血液之间的相互作用 血管和骨形成细胞。我们最近确定了骨骼的新生长因子 血管，Slit3。 Slit3由骨形成细胞产生，并增加骨形成 不是通过靶向骨形成细胞本身，而是通过促进血液生长 依次支持骨形成的血管。因此，slit3提出了一个有吸引力的研究工具 哪些血管在骨骼中影响骨骼形成以及这些血管如何塑造 产生骨形成细胞。此外，了解骨骼茎的最新进展 来自我们自己的细胞和其他人确定骨骼包含多个干细胞群 引起骨形成细胞，每个干细胞中的每个干细胞都有不同的解剖 位置和功能。单一类型的血管不太可能支持所有 这些不同的骨骼干细胞群体，因此我们假设不同 骨骼血管的类型每种支持不同类型的骨骼干细胞。在这里，slit3 既解决这一假设，又建立了内皮细胞的基本范例 支持骨形成。在AIM 1中，我们将研究Slit3介导的骨骼血的生长 容器是由已知促进骨形成的信号驱动的，确定了该裂缝3驱动的 需要对这些信号的骨形成反应的血管生长，也需要 哪些骨形成细胞的子集是SLIT3的关键生产商 回答。在AIM 2中，我们将确定每个特定的骨形成细胞都由每个特定的骨骼形成细胞支持 Slit3诱导的血管类型。在AIM 3中，我们将确定裂缝3诱导的血液如何 血管塑造了骨形成细胞的分化。总体而言，这项工作将提供 靶向骨骼血管的药物开发的基础 治疗骨质疏松症和其他骨骼疾病。 呢