"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: 10347187
• 负责人: Matthew Blake Greenblatt
• 金额: $ 36.92万
• 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/10347187
• 关键词: Address; Adopted; Anatomy; Angiogenic Factor; Area; Automobile Driving; Blood; Blood Vessels; Categories; 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 Transduction; Source; Stimulus; Structure; Supporting Cell; Testing; Therapeutic; Transplantation; Vascular Endothelial Cell; Vascular Endothelium; Work; angiogenesis; arteriole; base; bone; bone fracture repair; bone growth factor; bone loss; cell type; cellular targeting; drug development; mouse model; new growth; novel; novel strategies; prevent; 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 最近的研究表明，骨骼血管不仅是血液的通道，而且 相反，它在支持骨骼形成方面发挥着积极的作用。然而，目前尚不清楚哪些类型的 血管提供这种支持，这些血管如何改变骨的产生 从它们的干细胞前体形成细胞，或者血管和血管之间的这种耦合 骨形成细胞与骨形成的整体生理需求密切相关。这方面的进展 骨骼中血管的大部分生长因子也阻碍了这一区域的发展 直接作用于骨形成细胞，阻止其用于研究血液之间的相互作用 血管和骨形成细胞。我们最近发现了一种新的骨骼生长因子 血管，SLIT3。SLIT3由骨形成细胞产生，促进骨形成 不是通过针对骨形成细胞本身，而是通过促进血液的分泌 反过来支持骨形成的血管。因此，SLIT3是一个很有吸引力的研究工具 骨中哪些血管影响骨形成，以及这些血管如何塑造骨形成 骨形成细胞的产生。此外，了解骨骼干的最新进展 来自我们自己和其他人的细胞确定骨骼包含多种干细胞群体 形成骨形成细胞，每一种干细胞都有不同的解剖结构 位置和功能。一种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，我们相应地假设不同 不同类型的骨骼血管支持不同类型的骨骼干细胞。这里，SLIT3 既要解决这一假设，又要建立内皮细胞如何 支持骨骼形成。在目标1中，我们将研究SLIT3如何介导骨骼血的生长 血管是由已知促进骨形成的信号驱动的，决定这种SLIT3驱动的 血管生长是骨形成对这些信号的反应所必需的，而且 骨形成细胞的哪些亚群是这些细胞所需的SLIT3的关键生产者 回应。在目标2中，我们将确定每个细胞支持哪些特定的骨形成细胞 SLIT3诱导的血管类型。在目标3中，我们将确定SLIT3如何诱导血液 血管塑造了骨形成细胞的分化。总体而言，这项工作将提供 开发以骨骼血管为靶向的药物作为一种新的治疗方法的基础 治疗骨质疏松症和其他骨骼疾病。 好了！