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.

骨骼是我们体内最重要的结构之一。骨头让我们站起来， 步行并从一个地方移动到另一个地方，它们是我们重要器官的保护者。 我们的骨骼结构的降解 - 骨质疏松症 - 是一个全球健康问题。长期 我的研究的目标是了解控制骨骼的细胞和分子机制 开发，体内稳态和修复。目前，我们正在研究骨细胞的耦合 代谢活性感觉神经在骨发育和功能中的作用。 由我的优异评论奖支持的研究确定了一条新的途径 骨骼成骨细胞对全球燃料代谢和能量消耗的代谢活性。胰岛素 成骨细胞中的接收器信号传导调节骨钙素的生产和生物利用度 反过 响应能力。这种骨 - 五奈氏菌内分泌环的存在表明骨头 消耗了人体总体燃料供应的很大比例，因此 与其他消耗组织的竞争。目前，我们正在研究用 有选择地减弱葡萄糖或脂肪酸代谢的遗传改变。这些模型 将用于确定骨骼的燃料要求并确定能量的影响 在产后骨骼期间全球能量通量成骨细胞的底物氧化和代谢 开发和回应离散的合成代谢发作。这些代谢的重要性 途径是人类的代谢疾病，例如糖尿病和 内分泌控制机制中由遗传或环境灾害引起的骨质疏松症。 在NIH赞助的另一个项目中，我们正在研究感觉神经在骨头上的作用 开发和维修。开发组织决定了他们需要的神经的数量和类型 通过分泌神经营养蛋白，该神经营养通过激活不同的酪氨酸激酶来促进神经元存活 接收者。我们表明神经生长因子（NGF）通过神经营养酪氨酸激酶信号传导 受体1型（TRKA）指导发育中的小鼠股骨的神经支配以促进血管形成 和骨基源谱系进展。在初级骨化开始时，TRKA阳性轴突 穿透围骨骨表面，与中心相邻的细胞中的NGF表达一致 初期骨化。 TRKA（F592a）小鼠胚胎发生过程中TRKA信号传导的失活 神经受损，原发性和次级骨化中心的血管侵袭延迟， 扩大了表达OSX的骨基因生成剂的数量，并扩大了股骨长度和体积。 在他莫昔芬引起的破坏后，在小鼠中观察到了这些相同的表型异常 在表达COL2的骨软骨祖细胞中NGF的NGF。这些发现表明 NGF用作骨骼神经营养蛋白，以促进发育长骨的感觉神经 正常原发性和次级骨化的过程至关重要。同样，播放了NGF-Trka信号 在有条件的TRKA等位基因设计的小鼠中，在断裂修复过程中的重要作用。 ngf- 在软愈伤组织中积累的丰富种群，逐步积累 CGRP+ TRKA+感觉神经纤维在反应性骨膜内，在骨膜之前的时间点 血管化，骨化和矿化。时间抑制TRKA催化活性 随着时间的推移，将1NMPP1施用至TRKAF592A小鼠显着减少 感觉纤维，钝性的血运重建和愈合延迟。延迟响应 在用顺铂治疗后，在小鼠中也观察到骨折以诱导神经病。