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（多孔性骨病）是一种骨骼疾病，可对许多人造成衰弱影响。 美国退伍军人据估计，4400万美国人，即50岁及以上人口的55%， 目前有骨折的危险改善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状态。我的研究项目 利用了导致高骨量的人类疾病。这些高骨的遗传原因 肿块性疾病--颅管骨质增生症、硬化性骨质疏松症、货车布氏病--提供了对 可以对骨质疏松患者的骨量进行处理，以改善他们的骨骼健康并防止骨折。 许多与高骨量相关的疾病是由细胞信号传导途径的突变引起的， “Wnt”因此，操纵Wnt通路对骨骼健康的改善有很大的希望。这条路- 作为一种治疗靶点，这种方法特别有吸引力，因为它可以被操纵来增加新骨， 信息，而不是简单地防止进一步的骨质流失（这是如何所有，但目前可用的FDA- 经批准的治疗方法）。我的研究计划的长期目标是双重的：首先，我们寻求根据- 说明分泌的Wnt信号传导抑制剂如何作为协调单位发挥作用（即，环境），通过调整 当调节该单元的其它成员时它们的表达水平（例如，禁止或删除）。那些调整- 在欧盟成员国中表达意见是制定大规模 骨合成代谢作用的变化，如我们的支持数据所示。我们还试图了解这是如何 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， 对骨骼有持久的好处。我们试图了解抑制环境的某些成员是否起作用- 作为“归巢信号”，以确保新骨被添加到最需要的地方-高应变区域 并且它不被添加到不需要的地方-骨的低应变区域。再次，我们的 数据表明Wnt抑制环境在该过程中起重要作用。我们的第二个目标是- 针对Wnt抑制剂环境的导管功能研究，对未来的治疗应用具有直接适用性， 在病人中传播。骨消耗状况，如机械废用（例如，卧床休息，瘫痪）和葡萄糖- 皮质激素治疗（一种用于治疗炎症和免疫抑制的药物）在兽医中很常见， ans.根据我们和其他人对Wnt β i表达变化的测量， 在废用和糖皮质激素暴露后，我们假设四个Wnt的“代偿环境” Sost，Dkk 1，sFrp 4和Wise通过未知机制协调，以防止合成代谢作用， 存在废用糖皮质激素治疗。我们正在积极地以不同的组合瞄准整个环境- 为了确定我们是否可以恢复暴露在这些骨消耗条件下的小鼠的合成代谢活性， 选择。如果是这样的话，这些方法将对旨在治疗的治疗方法的设计产生深远的影响。 患有废用性和糖皮质激素引起的骨质疏松症的退伍军人。我们确定的另一个目标是， 也利用Wnt抑制剂环境的生物学，是为了确定我们是否可以减少剂量， 通过额外阻断通路产生显著合成代谢反应所需的Sost抗体体积 作为代偿环境的一部分的Sory Wnt抑制剂。我们已经证明我们可以显着地 增加Dkk 1抗体的合成代谢功效，如果我们在Sost抑制存在下使用它。殷切地盼望 如果我们同时阻断其他辅助作用， ry Wnt抑制剂。所描述的整体研究计划解决了这些问题，以确定新的 改善退伍军人群体和一般公众骨骼健康的方法。