"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. !

项目总结/摘要 最近的研究表明，骨骼血管不仅仅是血液的通道， 而是在支持骨形成中起积极作用。然而，不知道哪些类型的 血管提供这种支持，这些血管如何改变骨骼的产生 从它们的干细胞祖细胞形成细胞，或者这种血管和 骨形成细胞与骨形成的总体生理需求相关。的进展 骨中血管的大部分生长因子也阻碍了该区域的生长， 对骨形成细胞的直接影响，阻止它们用于研究血液与 血管和骨形成细胞。我们最近发现了一种新的骨骼肌生长因子， 血管，SLIT 3。SLIT 3由骨形成细胞产生并增加骨形成 不是通过针对骨形成细胞本身，而是通过促进血液的生长， 这些血管反过来又支持骨形成。因此，SLIT 3提供了一个有吸引力的研究工具 骨中的哪些血管影响骨形成，以及这些血管如何塑造骨形成。 生成骨形成细胞。此外，最近在了解骨骼干细胞方面的进展， 我们自己和其他人的干细胞鉴定出骨骼含有多个干细胞群， 这些干细胞中的每一种都具有不同的解剖结构， 位置和功能。单一类型的血管不太可能支持所有的血管。 这些不同的骨骼干细胞群，我们因此假设，不同的骨骼干细胞群， 不同类型的骨骼血管各自支持不同类型的骨骼干细胞。在这里，SLIT 3 为了解决这一假设，并建立内皮细胞如何 支持骨形成。在目的1中，我们将研究SLIT 3介导的骨骼血生长如何影响骨骼血的生长。 血管由已知促进骨形成的信号驱动，确定这种SLIT 3驱动的 骨形成对这些信号的反应需要血管生长 骨形成细胞的哪些亚群是这些所需的SLIT 3的关键生产者， 应答在目标2中，我们将确定每个细胞支持哪些特定的骨形成细胞， SLIT 3诱导的血管类型。在目标3中，我们将确定SLIT 3如何诱导血液 血管形成骨形成细胞的分化。总的来说，这项工作将提供一个 为开发针对骨骼血管的药物奠定了基础， 治疗骨质疏松症和其他骨骼疾病。 !