BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

基本信息

批准号：
10594018
负责人：
ALEXANDER G ROBLING
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594018
关键词：
Address Age Age Years Alcohol consumption American Anatomy Antibodies Award Basic Science Bed rest Biochemical Biography Biology Body Weight Bone Diseases Bone Tissue Cell physiology Cellular biology Compensation Country Data Dioxins Disease Dose Drug usage Environmental Risk Factor Event Exposure to Fracture Funding Future Genes Genetic Glucocorticoids Goals Health Healthcare Herbicides Home Homing Hormonal Hydrolase Hyperostosis Immunosuppression Impairment Indiana Inflammation Injury Investigation Journals Measurement Mechanical Stimulation Mechanics Mediator Medicine Metabolic Middle East Military Personnel Minerals Mission Mus Muscle Musculoskeletal Mutation Nature Osteoblasts Osteocytes Osteogenesis Osteoporosis Osteoporotic PTH gene Paper Paralysed Pathway interactions Patients Persian Gulf Persons Play Porosity Predisposition Process Property Proteins Publications Publishing Quantitative Trait Loci Rehabilitation therapy Reporting Research Research Personnel Risk Role Scientist Seminal Serum Side Signal Pathway Signal Transduction Skeleton Soldier Spinal cord injury Stimulus Structure Techniques Testosterone Tetrachlorodibenzodioxin Therapeutic Translational Research Universities Van Buchem disease Veterans Vietnam WNT Signaling Pathway War Wasting Syndrome Work agent orange arthropathies bone bone disuse atrophy bone health bone loss bone mass bone metabolism bone preservation bone strength career disability disease-causing mutation driving force genetic linkage genomic locus human disease improved inhibitor insight lifestyle factors long bone mechanical load mechanical signal mechanotransduction medical schools member military veteran mouse genome neuromuscular neuromuscular function neuromuscular rehabilitation novel strategies osteoporosis with pathological fracture physical inactivity prevent programs receptor response side effect skeletal skeletal disorder smoking prevalence therapeutic target therapy design translational medicine translational potential

项目摘要

Osteoporosis (porous bone disease) is a disease of the skeleton that can have debilitating effects on many US veterans. An estimated 44 million Americans, or 55 percent of the people 50 years of age and older, are currently at risk for osteoporotic fracture. Improved treatment options for the disease require a greater understanding of the cellular events and signaling pathways that control bone metabolism. The proposed research capitalizes on human diseases that result in very high bone mass. The genetic causes of these high bone mass diseases—craniotubular hyperostosis, hyperostosis corticalis, sclerosteosis, van Buchem’s disease—provide insight into how bone mass can be manipulated in osteoporotic patients to improve their skeletal health and prevent fractures. Many of the high-bone-mass associated diseases are caused by mutations in a cell signaling pathway called “Wnt.” Thus, manipulation of the Wnt pathway holds great promise for skeletal health improvement. This pathway is particularly attractive as a therapeutic target because it can be manipulated to increase new bone formation, rather than simply prevent further bone loss. The long term goals of the proposed project are twofold: first, we seek to understand how the secreted inhibitors of Wnt signaling function as a coordinated unit (i.e., a milieu), by adjusting their expression levels when other members of the unit are adjusted (e.g., inhibited or deleted). Those adjustments in expression in the members of the milieu represent prime targeting opportunities to enact large changes in anabolic action in bone, as our supporting data suggest. We also seek to understand how this Wnt inhibitor milieu controls the anabolic action of mechanical loading—a potent anabolic stimulus that has lasting benefits to the skeleton. We seek to understand whether certain members of the inhibitory milieu function as “homing signals” to ensure that new bone is added where it is needed most – to the high strain regions of the bone, and that it is not added where it is not needed – to the low strain regions of the bone. Again, our data suggest that the Wnt inhibitory milieu plays a significant role in this process. Our second goal of the application is to conduct functional studies targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic approaches in patients. Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and glucocorticoid therapy (a drug used for treating inflammation and immunosuppression) are common among veterans. Based on measurements we and others have made regarding the changes in expression of Wnt inhibitors following disuse and glucocorticoid exposure, we hypothesize that the “compensatory milieu” of four Wnt inhibitors–Sost, Dkk1, sFrp4, and Wise—coordinate via unknown mechanisms to prevent anabolic action in the presence of disuse glucocorticoid therapy. We propose to target the entire milieu in different combinations, to determine whether we can restore anabolic activity in mice exposed to these bone wasting conditions. If so, those studies would have far-reaching implications for the design of therapies aimed at treating veterans with disuse- and glucocorticoid-induced bone deficiencies. Another functional study we will undertake, which also capitalizes on the biology of the Wnt inhibitor milieu, is to determine whether we can reduce the dose/volume of Sost antibody required to generate a significant anabolic response by additionally blocking accessory Wnt inhibitors that are part of the compensatory milieu. We have already shown that we can dramatically increase the anabolic efficacy of Dkk1 antibody if we use it in the presence of Sost inhibition. We found another inhibitor that also might participate in compensation – a secreted member of the α/β-hydrolase superfamily known as Notum. We anticipate a significant osteoanabolic effect using much lower doses of antibody if we simultaneously block other accessory Wnt inhibitors. In this renewal Merit application, we address these questions in order to identify new ways to improve bone health among the veteran population, and among the public in general.

骨质疏松症（多孔骨病）是一种骨骼疾病，可能对许多美国人造成衰弱影响据估计，有 4400 万美国人，即 50 岁及以上人口的 55% 是退伍军人。目前处于骨质疏松性骨折风险的患者需要更大的改进治疗方案。了解控制骨代谢的细胞事件和信号通路。研究利用了导致高骨量的人类疾病的遗传原因。骨量疾病——颅管骨质增生、皮质骨质增生、硬化症、van Buchem’s 疾病——深入了解如何控制骨质疏松症患者的骨量以改善他们的骨质疏松症骨骼健康和预防骨折许多与高骨量相关的疾病都是由高骨量引起的。称为“Wnt”的细胞信号传导通路发生突变。因此，对 Wnt 通路的操纵具有巨大的前景。该途径作为治疗靶点特别有吸引力，因为它可以从长远来看，通过操纵来增加新骨的形成，而不是简单地防止进一步的骨质流失。该项目的目标有两个：首先，我们试图了解 Wnt 的分泌抑制剂如何信号传导功能作为一个协调单位（即环境），通过在其他情况下调整其表达水平该单位的成员被调整（例如，抑制或删除）。环境的变化代表了对骨骼合成代谢作用进行重大改变的主要目标机会，因为我们支持数据表明，我们还试图了解这种 Wnt 抑制剂环境如何控制合成代谢作用。机械负荷——一种对骨骼具有持久益处的有效合成代谢刺激。了解抑制环境中的某些成员是否发挥“归巢信号”的作用，以确保新的骨骼被添加到最需要的地方 - 骨骼的高应变区域，而不是添加到最需要的地方是不需要的区域——对于骨骼的低应变，我们的数据再次表明 Wnt 抑制环境。我们应用程序的第二个目标是进行功能研究。靶向 Wnt 抑制剂环境，可直接适用于未来的患者治疗方法。骨消耗情况，例如机械废用（例如卧床休息、瘫痪）和糖皮质激素治疗（a 用于治疗炎症和免疫抑制的药物）在退伍军人中很常见。我们和其他人对 Wnt 抑制剂表达的变化进行了测量通过废用和糖皮质激素暴露，我们捕获了四种 Wnt 抑制剂的“补偿环境”——Sost、 Dkk1、sFrp4 和 Wise — 通过未知机制进行协调，以防止存在合成代谢作用我们建议以不同的组合针对整个环境，以确定是否停用糖皮质激素治疗。我们是否可以恢复暴露于这些骨消耗条件下的小鼠的合成代谢活性如果可以，那么这些研究。将对治疗退伍军人的疗法设计产生深远的影响我们将进行另一项功能性研究，该研究也利用了糖皮质激素引起的骨缺陷。 Wnt 抑制剂环境的生物学，是确定我们是否可以减少 Sost 的剂量/体积通过另外阻断辅助 Wnt 抑制剂来产生显着的合成代谢反应所需的抗体这是补偿环境的一部分，我们已经证明我们可以大幅提高如果我们在 Sost 抑制存在的情况下使用 Dkk1 抗体的合成代谢功效，我们发现了另一种抑制剂。也可能参与补偿——α/β-水解酶超家族的一个分泌成员，称为 Notum，如果我们使用更低剂量的抗体，我们预计会产生显着的骨合成代谢效果。同时阻断其他辅助 Wnt 抑制剂在本次更新 Merit 申请中，我们解决了这些问题。问题，以确定改善退伍军人和老年人骨骼健康的新方法一般公众。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1.

DOI：
10.1096/fj.202000713rr
发表时间：
2020-09
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Liu S;Wu D;Sun X;Fan Y;Zha R;Jalali A;Teli M;Sano T;Siegel A;Sudo A;Agarwal M;Robling A;Li BY;Yokota H
通讯作者：
Yokota H