BLRD Research Career Scientist Award Application

摘要 我的SRCS计划的这一竞争性续订申请侧重于以下三个主要的健康问题 VA患者群体、脑外伤、骨质疏松症和骨性关节炎。我们关注的其中一个主要领域是长期- 创伤性脑损伤对骨骼的长期负面影响。颅脑损伤，战斗行动的标志性伤病，结果 在无数的临床并发症中，这些并发症对我们的战场战士们造成了毁灭性的影响，并代表了一个 在CRADO的五个交叉临床优先事项中。在我们的研究中，我们已经确定了重复性轻度脑损伤 通过影响峰值骨量，对骨骼系统长期产生显著的负面影响 并通过促进损伤后软组织异位成骨。我们目前的研究主要集中在 阐明关键的细胞元件和相关的系统和局部信号通路，影响 异位骨对颅脑损伤和局部创伤的反应，旨在开发新的治疗方法 脑外伤患者异位骨化的防治策略。 老年退伍军人的人数继续增加，因此，影响老年人的问题 成为退伍军人管理局研究的优先事项。骨质疏松症和骨性关节炎(OA)是与年龄相关的重大公共卫生问题 这些问题给退伍军人和普通美国人带来了巨大的经济负担。它是 据估计，在50岁及以上的女性中，约有1/2的女性和1/4的男性会因为 骨质疏松。众所周知，骨质疏松症和骨性关节炎的发病机制在美国影响着3000多万成年人。 已知包括骨和软骨的破坏增加，而不是由平行增加的 新组织的合成。因此，我的退伍军人事务部和美国国立卫生研究院赞助的研究的长期目标集中在 确定导致老年人骨和软骨丢失的信号通路缺陷，并 开发新的合成代谢策略来治疗这些衰弱的骨骼疾病。 多年来，我们的实验室卓有成效，发表了370篇同行评议研究文章，30篇评论 文章和28个书章。我们的出版物收到了超过45,000次引用，H因子为89 而I-10指数为839。我们的研究在骨骼和矿物领域有了几个重要的发现 在30年的时间里，他一直从联邦机构(退伍军人事务部、美国国立卫生研究院、美国国防部)获得资金。 我是2017年度ASBMR Louis AVii创始人奖的获得者，以表彰他的终身贡献 在与骨骼和矿物质代谢相关的翻译研究中。除了建立强大的主动权 通过本地和全国的合作，我们的计划继续成功地指导新一代 研究人员，并在地方和国家层面上为退伍军人管理局的研究管理做出贡献。我们正在进行的 研究的目的不仅是为了提供对关键信号通路在体内的作用的机械性见解 对各种骨消耗性疾病的病理生理学研究，也是为了确定新的和合理的药物靶点 开发新的有效疗法来治疗影响退伍军人健康的代谢性骨病。

SUMMARY This competitive renewal application of my SRCS program is focused on three major health problems in the VA patient population, TBI, osteoporosis and osteoarthritis. One of our major areas of focus is on the long- term negative impact of traumatic brain injury (TBI) on bone. TBI, a signature injury of combat operations, results in a myriad of clinical complications that have devastating effects on our battlefield warriors and represents one of CRADO’s five cross-cutting clinical priorities. In our studies, we have established that repetitive mild TBI exerts a significant negative impact on the skeletal system over the long term by influencing peak bone mass and by promoting ectopic bone formation in soft tissues after injury. Our current studies are focused on elucidating the key cellular elements and the relevant systemic and local signaling pathways that impact the development of ectopic bone in response to TBI and local trauma with a goal of developing novel therapeutic strategies for prevention and treatment of heterotopic ossification in TBI patients. The population of elderly veterans continues to increase, and, therefore, issues affecting the aged have become a VA research priority. Osteoporosis and osteoarthritis (OA) are significant age-related public health problems in the Veterans as well as in the general U.S. population and pose a substantial financial burden. It is estimated that approximately one in two women and one in four men age 50 and older will break a bone due to osteoporosis. OA is known to affect over 30 million adults in the U.S. The pathogenesis of osteoporosis and OA are known to involve increased destruction of bone and cartilage, not compensated by parallel increases in the synthesis of new tissue. Therefore, the long-term goals of my VA- and NIH-sponsored research is focused on identifying the defective signaling pathways that contribute to bone and cartilage loss in the elderly, and to develop novel anabolic strategies for treatment of these debilitating bone diseases. Our laboratory has been very productive over the years with 370 peer review research articles, 30 review articles and 28 book chapters. Our publications have received more than 45,000 citations with an H-factor of 89 and an i-10-index of 839. Our research has led to several important discoveries in the areas of bone and mineral metabolism and has received continuous funding from federal agencies (VA, NIH, DOD) over a span of 30 years. I was the recipient of the 2017 ASBMR Louis Avioli Founder’s award given in recognition of life-long contributions in translational research related to bone and mineral metabolism. Besides establishing strong active collaborations both locally and nationally, our program continues to successfully mentor a new generation of researchers and contributes to VA research administration at both a local and national level. Our ongoing studies are designed to not only provide mechanistic insights into the role of the key signaling pathways in the pathophysiology of the various bone-wasting diseases but also to identify novel and rational drug targets for the development of novel effective therapies to treat metabolic bone diseases that impact the health of veterans.