BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9898310
• 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/9898310
• 关键词: Address; Afghanistan; Age; Age-Years; Alcohol consumption; 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; Wasting Syndrome; Work; adjudication; agent orange; arthropathies; base; 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/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; side effect; skeletal; smoking prevalence; therapeutic target; therapy design; translational medicine

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（多孔骨疾病）是骨骼的疾病，可能对许多人产生令人衰弱的影响 美国退伍军人。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的不足 控制骨代谢的细胞事件和信号通路的站立。我的研究计划 利用导致骨骼很高的人类疾病。这些高骨头的遗传原因 群众疾病 - 颅管性肿瘤，硬化症，范布切姆氏病 - 提供了有关如何 可以在骨质疏松患者中操纵骨骼肿块，以改善其骨骼健康并预防骨折。 许多高骨质量相关疾病是由称为的细胞信号通路中的突变引起的 “ Wnt。”这是WNT途径的操纵对骨骼健康改善的巨大希望。这个路径 - 作为治疗靶标的方式特别有吸引力，因为它可以操纵以增加新的骨骼 交流，而不是简单地防止进一步的骨质流失（这是当前可用的FDA-除 批准的疗法工作）。我的研究计划的长期目标是双重的：首先，我们试图低估 通过调整WNT信号传导的秘密抑制剂如何作为协调单元（即环境）来调整 当调整单元的其他成员（例如，抑制或删除）时，它们的表达水平。那些调整 - 环境成员的表达方式代表了制定大型目标的主要目标机会 正如我们的支持数据所表明的那样，骨骼中合成代谢作用的变化。我们也试图了解如何 WNT抑制剂环境控制机械负载的合成代谢作用，这是一种有效的合成代谢刺激 骨骼的持久利益。我们试图了解抑制性环境的某些成员是否能力 - 作为“归巢信号”，以确保最需要的地方添加新骨头 - 高应变区域 骨头，并且不在不需要的地方添加它 - 骨头的低应变区域。再次，我们的 数据表明，WNT抑制环境在此过程中起着重要作用。我们的第二个目标是 针对Wnt抑制剂环境的导管功能研究，该研究直接适用于将来的治疗性AP- 患者的侵害。浪费骨浪费条件，例如机械废物（例如，卧床，瘫痪）和葡萄糖 在兽医中常见皮质疗法（一种用于治疗注射和免疫抑制的药物）很常见 Ans。根据我们和其他人对Wnt抑制的表达变化所做的测量 废弃和糖皮质激素暴露后的TOR，我们假设四个Wnt的“补偿环境” 抑制剂-SOST，DKK1，SFRP4和WISE - 通过未知机制进行隔离，以防止代谢作用 废除糖皮质激素治疗的存在。我们正在积极针对不同组合的整个环境 为了确定我们是否可以恢复暴露于这些骨骼浪费的小鼠中的合成代谢活性 tions。如果是这样，这些方法将对旨在治疗的疗法设计具有深远的影响 - 用废弃和糖皮质激素引起的骨缺陷的退伍军人。我们定义的另一个目标，这是 还要利用Wnt抑制剂环境的生物学，是确定我们是否可以减少剂量/ 通过额外阻止访问 - 属于补偿性环境一部分的Sory Wnt抑制剂。我们已经表明我们可以急剧 如果我们在存在SOST抑制作用的情况下使用DKK1抗体的合成代谢效率。我们期待一个 如果我们简单地阻止其他访问权限，则使用较低剂量的抗体使用明显的骨代谢作用 ry wnt抑制剂。描述的整体研究计划解决了这些问题，以确定新的问题 改善退伍军人人口以及一般公众中的骨骼健康的方法。