BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10515312
• 负责人: Thomas L Clemens
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515312
• 关键词: Affect; Alleles; Attenuated; Award; Axon; Biological Availability; Blood Vessels; Bone Development; Bone Diseases; Bone Surface; Bone callus; Bone structure; Cells; Cisplatin; Communication; Consumption; Coupling; Diabetes Mellitus; Embryonic Development; Endocrine; Energy Metabolism; Energy consumption; Engineering; Femur; Fiber; Fracture; Genetic; Glucose; Goals; Grant; Homeostasis; Human; Impairment; Insulin; Insulin Receptor; Invaded; Length; Link; Macrophage; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Molecular; Mus; Mutation; Nerve Block; Nerve Fibers; Nerve Growth Factors; Neuropathy; Neurotrophic Tyrosine Kinase Receptor Type 1; Organ; Osteoblasts; Osteocalcin; Osteocytes; Osteoporosis; Pancreas; Pathway interactions; Penetration; Periosteum; Peripheral; Phenotype; Physiologic Ossification; Play; Population; Prevention; Process; Production; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Research; Role; Scientist; Sensory; Signal Transduction; Skeletal Development; Skeleton; Stimulus; Structure; Tamoxifen; Time; Tissues; Tyrosine Kinase Receptor Inhibition; Ulna Fractures; United States National Institutes of Health; Vascularization; Walking; afferent nerve; bone; bone cell; bone fracture repair; bone repair; career; fatty acid metabolism; global health; insulin secretion; long bone; mineralization; mouse model; nerve supply; neuronal survival; neurotrophic factor; novel; novel strategies; osteochondral tissue; osteoprogenitor cell; oxidation; panacea; postnatal; progenitor; repaired; response; skeletal; stromal progenitor

The skeleton is one of the most important structures in our bodies. Bones allow us to stand, walk and move from one place to another, and they serve as protectors of our vital organs. Degradation of our bones structure — osteoporosis — is a global health problem. The long-term goal of my research is to understand the cellular and molecular mechanisms governing skeletal development, homeostasis and repair. Currently, we are studying the coupling of bone cell metabolic activity the role of sensory nerves in bone development and function. Studies supported by my Merit Review Award identified a novel pathway that links the metabolic activity of skeletal osteoblasts to global fuel metabolism and energy expenditure. Insulin receptor signaling in the osteoblast regulates the production and bioavailability of osteocalcin, which in turn, acts in an endocrine fashion to regulate pancreatic insulin secretion and peripheral insulin responsiveness. The existence of this bone-panaceas endocrine loop suggests that bone consumes a significant proportion of the body’s overall fuel supply, and consequently is in competition with other energy consuming tissues. Currently, we are studying mouse models with genetic alterations that selectively attenuate either glucose or fatty acid metabolism. These models will be used to determine the fuel requirements of bone accrual and determine the impact of energy substrate oxidation and metabolism by osteoblasts on global energy flux during post-natal bone development and in response to discrete anabolic episodes. The importance of these metabolic pathways humans is profoundly illustrated by metabolic diseases such as diabetes and osteoporosis caused by genetic or environmental disturbances in endocrine control mechanisms. In another project sponsored by NIH we are investigating the role of sensory nerves on bone development and repair. Developing tissues dictate the amount and type of innervation they require by secreting neurotrophins, which promote neuronal survival by activating distinct tyrosine kinase receptors. We show that nerve growth factor (NGF) signaling through neurotrophic tyrosine kinase receptor type 1 (TrkA) directs innervation of the developing mouse femur to promote vascularization and osteoprogenitor lineage progression. At the start of primary ossification, TrkA-positive axons penetrate perichondrial bone surfaces, coincident with NGF expression in cells adjacent to centers of incipient ossification. Inactivation of TrkA signaling during embryogenesis in TrkA(F592A) mice impaired innervation, delayed vascular invasion of the primary and secondary ossification centers, decreased numbers of Osx-expressing osteoprogenitors, and decreased femoral length and volume. These same phenotypic abnormalities were observed in mice following tamoxifen-induced disruption of NGF in Col2-expressing perichondrial osteochondral progenitors. These findings indicate that NGF serves as a skeletal neurotrophin to promote sensory innervation of developing long bones, a process critical for normal primary and secondary ossification. Similarly, NGF-TrkA signaling played an important role during fracture repair in mice engineered with conditional TrkA alleles. NGF- enriched populations accumulated within the soft callus with progressive accumulation of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum, at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice over time of fracture significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed consolidation of the callus. Delayed response to fracture was also observed in mice following treatment with cisplatinum to induce neuropathy.

骨骼是我们身体最重要的结构之一。骨头让我们站立， 从一个地方步行并移动到另一个地方，它们是我们重要器官的保护者。 我们骨骼结构的退化——骨质疏松症——是一个全球性的健康问题。长期来看 我的研究目标是了解控制骨骼的细胞和分子机制 发育、稳态和修复。目前我们正在研究骨细胞的耦合 代谢活动感觉神经在骨骼发育和功能中的作用。 由我的优异评审奖支持的研究确定了一条将 骨骼成骨细胞的代谢活动对整体燃料代谢和能量消耗的影响。胰岛素 成骨细胞中的受体信号传导调节骨钙素的产生和生物利用度，骨钙素 反过来，以内分泌方式发挥作用，调节胰腺胰岛素分泌和外周胰岛素 反应能力。这种骨灵丹妙药内分泌循环的存在表明骨 消耗身体总燃料供应的很大一部分，因此处于 与其他耗能组织的竞争。目前，我们正在研究小鼠模型 选择性减弱葡萄糖或脂肪酸代谢的基因改变。这些型号 将用于确定骨生成的燃料需求并确定能量的影响 成骨细胞的底物氧化和代谢对出生后骨期间整体能量通量的影响 发育和对离散合成代谢事件的反应。这些代谢的重要性 糖尿病等代谢疾病深刻地说明了人类的通路 由遗传或环境内分泌控制机制紊乱引起的骨质疏松症。 在 NIH 赞助的另一个项目中，我们正在研究感觉神经对骨骼的作用 开发和修复。发育中的组织决定了它们所需的神经支配的数量和类型 通过分泌神经营养素，通过激活不同的酪氨酸激酶来促进神经元存活 受体。我们发现神经生长因子（NGF）信号通过神经营养酪氨酸激酶 1 型受体 (TrkA) 指导发育中小鼠股骨的神经支配以促进血管化 和骨祖细胞谱系进展。在初级骨化开始时，TrkA 阳性轴突 穿透软骨膜骨表面，与邻近中心的细胞中的 NGF 表达一致 早期骨化。 TrkA (F592A) 小鼠胚胎发生过程中 TrkA 信号失活 神经支配受损，初级和次级骨化中心的血管侵袭延迟， 表达 Osx 的骨祖细胞数量减少，股骨长度和体积减少。 在他莫昔芬诱导的破坏后，在小鼠中观察到这些相同的表型异常 表达 Col2 的软骨膜骨软骨祖细胞中 NGF 的作用。这些发现表明 NGF 作为骨骼神经营养蛋白，促进长骨发育的感觉神经支配， 对于正常的初级和次级骨化至关重要的过程。类似地，NGF-TrkA 信号发挥作用 在带有条件 TrkA 等位基因的小鼠骨折修复过程中发挥着重要作用。 NGF- 随着逐渐积累，软愈伤组织内积累了丰富的种群 反应性骨膜内的 CGRP+TrkA+ 感觉神经纤维，在骨膜之前的时间点 血管化、骨化和矿化。 TrkA 催化活性的暂时抑制 随着骨折时间的推移，对 TrkAF592A 小鼠施用 1NMPP1 显着减少了 感觉纤维、血运重建迟缓和骨痂固结延迟。反应迟缓 在用顺铂治疗诱导神经病变后，也观察到小鼠骨折。