BLR&D Research Career Scientist Award Application

骨骼是我们身体中最重要的结构之一。骨头让我们可以站立， 行走和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。 我们骨骼结构的退化--骨质疏松症--是一个全球健康问题。长期的 我的研究目标是了解控制骨骼的细胞和分子机制 发展、动态平衡和修复。目前，我们正在研究骨细胞的偶联 代谢活动感觉神经在骨骼发育和功能中的作用。 由我的功绩评审奖支持的研究发现了一条新的途径，将 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 成骨细胞中的受体信号调节骨钙素的产生和生物利用度，这是 反过来，以内分泌方式调节胰腺胰岛素分泌和外周胰岛素 响应性。这种骨骼-万能药内分泌环路的存在表明，骨骼 消耗身体总燃料供应的很大一部分，因此在 与其他耗能组织竞争。目前，我们正在研究老鼠模型 选择性地减弱葡萄糖或脂肪酸新陈代谢的基因改变。这些型号 将用于确定骨积累量的燃料需求和确定能量的影响 生后成骨细胞底物氧化代谢对整体能量流的影响 发展和对离散的合成代谢发作的反应。这些新陈代谢的重要性 代谢疾病，如糖尿病和糖尿病，深刻地说明了人类的途径 骨质疏松症由内分泌控制机制中的遗传或环境干扰引起的。 在NIH赞助的另一个项目中，我们正在研究感觉神经在骨骼上的作用 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 通过分泌神经营养因子，通过激活不同的酪氨酸激酶促进神经元存活 感受器。我们发现神经生长因子(NGF)通过神经营养酪氨酸激酶信号转导 受体1型(TrkA)指导发育中小鼠股骨的神经支配以促进血管形成 以及骨祖细胞的世系进化。在初级骨化开始时，TrkA阳性轴突 穿透软骨膜表面，与中心附近细胞中NGF的表达一致 刚开始的骨化。TrkA(F592a)小鼠胚胎发生过程中TrkA信号的失活 神经受损，初级和次级骨化中心血管侵入延迟， 表达OSX的骨祖细胞数量减少，股骨长度和体积减少。 在他莫昔芬诱导的干扰后，在小鼠身上观察到了同样的表型异常 神经生长因子在表达COL2的软骨周围骨软骨前体细胞中的表达。这些发现表明， NGF是一种骨骼神经营养因子，可促进发育中的长骨的感觉神经支配 对正常的原发和继发骨化至关重要的过程。同样，NGF-TrkA信号也发挥了作用 在携带条件TrkA等位基因的小鼠的骨折修复过程中起着重要作用。NGF- 在软愈伤组织内积累丰富的种群，并逐渐积累 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催化活性的时间抑制 在TrkAF592a小鼠骨折后给予1NMPP1显著减少了小鼠的 感觉纤维、钝化的血运重建和延迟的骨痂固结。延迟响应 在用顺铂治疗神经病变的小鼠中也观察到了骨折的发生。

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.