BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9340863
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9340863
• 关键词: Address; Adverse effects; Afghanistan; Age; Age-Years; Alcohol consumption; Alpha Cell; American; Antibodies; Award; Bed rest; Biochemical; Biochemistry; Biology; Biomedical Engineering; Body Weight; Bone Diseases; Bone Tissue; Book Chapters; Data; Diagnosis; Dioxins; Disease; Dose; Drug usage; Endocrinology; Ensure; Environmental Risk Factor; Event; Exposure to; FDA approved; Fracture; Future; Genes; Genetic; Genome; Glucocorticoids; Goals; Health; Healthcare; Herbicides; Home environment; Homing; Hormonal; Hyperostosis; Immunosuppression; Impairment; Inflammation; Injury; Investigation; Iraq; Journals; Measurement; Mechanical Stimulation; Mechanics; Mediator of activation protein; Medicine; Metabolic; Military Personnel; Minerals; Mission; Mus; Muscle; Musculoskeletal; Mutation; Nature; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporotic; PTH gene; Paper; Paralysed; Pathway interactions; Patients; Persian Gulf; Plague; Play; Population; Post-Traumatic Stress Disorders; Predisposition; Prisoner; Process; Property; Proteins; Publications; Publishing; Quantitative Trait Loci; Regulation; Rehabilitation therapy; Reporting; Research; Risk; Role; Scientist; Seminal; Serum; Services; Signal Pathway; Signal Transduction; Skeleton; Soldier; Spinal cord injury; Stimulus; Structure; Techniques; Testosterone; Tetrachlorodibenzodioxin; Therapeutic; Time; Translational Research; Van Buchem disease; Veterans; Vietnam; WNT Signaling Pathway; War; Work; adjudication; agent orange; arthropathies; base; bone; bone disuse atrophy; bone health; bone loss; bone mass; bone metabolism; bone strength; career; disability; disease-causing mutation; driving force; genetic linkage; human disease; improved; inhibitor/antagonist; insight; lifestyle factors; long bone; mechanical load; mechanotransduction; member; neuromuscular; neuromuscular function; neuromuscular rehabilitation; novel strategies; osteoporosis with pathological fracture; physical inactivity; prevent; programs; receptor; response; skeletal; smoking prevalence; therapeutic target; therapy design; translational medicine; wasting

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 under- standing of the cellular events and signaling pathways that control bone metabolism. My research program capitalizes on human diseases that result in very high bone mass. The genetic causes of these high bone mass diseases—craniotubular hyperostosis, 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 path- way is particularly attractive as a therapeutic target because it can be manipulated to increase new bone for- mation, rather than simply prevent further bone loss (which is how all but one of the currently available FDA- approved therapies work). The long term goals of my research program are twofold: first, we seek to under- stand 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 adjust- ments 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 func- tion 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 is to con- duct functional studies targeting the Wnt inhibitor milieu, that have direct applicability to future therapeutic ap- proaches in patients. Bone wasting conditions such as mechanical disuse (e.g., bedrest, paralysis) and gluco- corticoid therapy (a drug used for treating inflammation and immunosuppression) are common among veter- ans. Based on measurements we and others have made regarding the changes in expression of Wnt inhibi- tors 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 are actively targeting the entire milieu in different combina- tions, to determine whether we can restore anabolic activity in mice exposed to these bone wasting condi- tions. If so, those approaches would have far-reaching implications for the design of therapies aimed at treat- ing veterans with disuse- and glucocorticoid-induced bone deficiencies. Another goal we have defined, 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 acces- sory 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 anticipate a significant osteoanabolic effect using much lower doses of antibody if we simultaneously block other accesso- ry Wnt inhibitors. The overall research program described addresses 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，可对许多人造成衰弱影响 据估计，美国有 4400 万退伍军人，即 50 岁及以上人口的 55%。 目前面临骨质疏松性骨折的风险，需要更好地改善该疾病的治疗方案。 我的研究项目是控制骨代谢的细胞事件和信号通路。 利用导致骨量非常高的人类疾病这些高骨的遗传原因。 群体性疾病——颅管骨质增生、硬化症、范布赫姆氏病——提供了关于如何 可以控制骨质疏松症患者的骨量，以改善其骨骼健康并预防骨折。 许多高骨量相关疾病是由细胞信号通路突变引起的，该通路称为 “Wnt。”因此，操纵 Wnt 通路对于改善骨骼健康有着巨大的希望。 作为一种治疗靶点，这种方式特别有吸引力，因为它可以被操纵以增加新骨： 化，而不是简单地防止进一步的骨质流失（这就是目前 FDA 批准的除一种药物之外的所有药物的方法） 我的研究计划的长期目标有两个：首先，我们寻求低于- 通过调整，了解 Wnt 信号传导的分泌抑制剂如何作为协调单元（即环境）发挥作用 当单元的其他成员被调整（例如，抑制或删除）时，它们的表达水平。 环境成员的表达意见是制定大规模行动的主要目标机会 正如我们的支持数据所表明的那样，我们还试图了解这是如何发生的。 Wnt 抑制剂环境控制机械负荷的合成代谢作用——一种有效的合成代谢刺激，具有 我们试图了解抑制性环境的某些成员是否发挥作用。 作为“归巢信号”，以确保将新骨添加到最需要的地方 - 高应变区域 骨骼的低应变区域，并且不会将其添加到不需要的地方。 数据表明 Wnt 抑制环境在此过程中发挥着重要作用。 针对 Wnt 抑制剂环境的导管功能研究，可直接应用于未来的治疗应用 患者的骨消耗情况，例如机械废用（例如卧床休息、瘫痪）和血糖升高。 皮质类固醇疗法（一种用于治疗炎症和免疫抑制的药物）在兽医中很常见 回答：根据我们和其他人对 Wnt 抑制剂表达变化所做的测量 在停用和糖皮质激素暴露后，我们发现四种 Wnt 的“补偿环境” 抑制剂——Sost、Dkk1、sFrp4 和 Wise——通过未知机制进行协调，以阻止合成代谢作用 我们正在积极针对整个环境进行不同的组合治疗。 ，以确定我们是否可以恢复暴露于这些骨消耗条件的小鼠的合成代谢活性 如果是这样，这些方法将对旨在治疗的疗法的设计产生深远的影响。 我们定义了另一个目标，即患有废用性和糖皮质激素引起的骨骼缺陷的退伍军人。 还利用 Wnt 抑制剂环境的生物学特性，确定我们是否可以减少剂量/ 通过额外阻断通路产生显着的合成代谢反应所需的 Sost 抗体体积 一些 Wnt 抑制剂是补偿环境的一部分，我们已经证明我们可以显着地发挥作用。 如果我们在存在 Sost 抑制的情况下使用 Dkk1 抗体，则会增加 Dkk1 抗体的合成代谢功效。 如果我们同时阻断其他辅助手段，则使用低得多剂量的抗体即可产生显着的骨合成代谢作用 整个研究计划描述了解决这些问题的目的，以便识别新的 Wnt 抑制剂。 改善退伍军人和一般公众骨骼健康的方法。