BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 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
• 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

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）是骨骼的疾病 退伍军人。估计有4400万美国人，或50岁以上的人中有55％是 目前有骨质疏松性骨折的风险。改善该疾病的治疗选择需要更大 了解控制骨代谢的细胞事件和信号通路。提议 研究资源的人类疾病，导致骨骼质量很高。这些高的遗传原因 骨质量疾病 - 颅管性高肠病，皮质病，硬化症，范布切姆的骨骼疾病 疾病 - 对如何在骨质疏松患者中如何操纵骨骼的洞察力来改善其 骨骼健康并预防骨折。许多高骨质量相关疾病是由 细胞信号通路中的突变称为“ Wnt”。那是Wnt途径的操纵具有巨大的希望 用于骨骼健康的改善。作为治疗目标，该途径特别有吸引力 被操纵以增加新的骨形成，而不是简单地防止进一步的骨质流失。长期 拟议项目的目标是双重的：首先，我们试图了解Wnt的分泌抑制剂如何 信号传导功能作为协调单元（即环境），当其他时调整其表达水平时 调整单元的成员（例如，抑制或删除）。成员表达的这些调整 MIRIEU代表了主要的目标机会，以实施骨骼的合成代谢作用发生巨大变化，作为我们的 支持数据建议。我们还试图了解该WNT抑制剂环境如何控制合成代谢作用 机械载荷 - 一种有效的合成代谢刺激，对骨架具有持久的益处。我们寻求 了解抑制环境的某些成员是否充当“归巢信号”以确保新的 在最需要的地方添加骨头 - 骨头的高应变区域，并且不会在它的位置添加 不需要 - 对于骨骼的低应变区域。同样，我们的数据表明WNT抑制环境 在此过程中起着重要作用。我们应用的第二个目标是进行功能研究 针对WNT抑制剂环境，该抑制剂对患者的未来治疗方法有直接适用。 浪费骨浪费条件，例如机械废物（例如床架，麻痹）和糖皮质激素治疗（a） 用于治疗注射和免疫抑制的药物在退伍军人中很常见。基于 我们和其他人对Wnt抑制剂表达的变化进行了测量 废除和糖皮质激素暴露，我们假设四个Wnt抑制剂的“代偿环境” - DKK1，SFRP4和WISE - 通过未知机制进行结合，以防止在存在的情况下合成代谢​​作用 废除糖皮质激素治疗。我们建议以不同的组合为目标，以确定 我们是否可以恢复暴露于这些骨骼浪费条件的小鼠中的合成代谢活性。如果是这样，那些研究 对旨在用废弃和治疗退伍军人的疗法的设计具有深远的影响 糖皮质激素诱导的骨缺陷。我们将进行的另一项功能性研究，这也大写了 Wnt抑制剂环境的生物学是确定我们是否可以减少剂量/体积 通过阻止附件Wnt抑制剂产生明显的合成代谢响应所需的抗体 是补偿环境的一部分。我们已经表明，我们可以大大增加 如果我们在存在较高的抑制作用的情况下使用DKK1抗体的合成代谢效率。我们发现了另一个抑制剂 也可能参与补偿 - α/β-Hydrollosy superfimily的分泌成员被称为 没有。如果我们，我们预计使用较低剂量的抗体会产生明显的骨代谢作用 类似地阻止其他附件Wnt抑制剂。在此续签功绩申请中，我们解决这些问题 问题以确定改善退伍军人人口的骨骼健康的新方法， 一般公开。

项目成果

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
• 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