BLRD Research Career Scientist Award Application

总结 我的SRCS计划的这种竞争性更新应用程序的重点是三个主要的健康问题， VA患者人群、TBI、骨质疏松症和骨关节炎。我们关注的主要领域之一是长期- 创伤性脑损伤（TBI）对骨骼的长期负面影响。TBI，战斗行动的标志性伤害，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具有毁灭性的影响， CRADO的五个交叉临床优先事项。在我们的研究中，我们已经确定了重复性轻度TBI 通过影响峰值骨量，长期对骨骼系统产生显著的负面影响 以及通过促进损伤后软组织中的异位骨形成。我们目前的研究集中在 阐明了关键的细胞元件和相关的系统和局部信号通路，影响 异位骨的发展对TBI和局部创伤的反应，目的是开发新的治疗方法， 预防和治疗TBI患者异位骨化的策略。 老年退伍军人的人口继续增加，因此，影响老年人的问题 成为研究重点。骨质疏松症和骨关节炎（OA）是与年龄相关的重要公共卫生问题 退伍军人以及美国普通民众的问题，并构成了巨大的财政负担。是 据估计，50岁及以上的女性和男性中，约有二分之一和四分之一会骨折， 骨质疏松已知OA影响美国超过3000万成年人。 已知涉及骨和软骨的破坏增加，而不是通过骨和软骨的平行增加来补偿。 新组织的合成。因此，我的VA和NIH赞助的研究的长期目标集中在 确定导致老年人骨和软骨损失的有缺陷的信号通路， 开发新的合成代谢策略来治疗这些使人衰弱的骨病。 多年来，我们的实验室一直非常富有成效，有370篇同行评审研究文章，30篇评审 28篇文章和28本书。我们的出版物已收到超过45，000次引用，H因子为89 和839的I-10指数。我们的研究在骨骼和矿物质领域有了一些重要的发现 代谢，并已收到连续的资助，从联邦机构（VA，NIH，国防部）超过30年的跨度。 我是2017年ASBMR Louis Avioli创始人奖的获得者，以表彰终身贡献 骨和矿物质代谢相关的转化研究。除了建立强大的主动 在地方和国家的合作，我们的计划继续成功地指导新一代的 研究人员，并有助于VA研究管理在地方和国家一级。我们正在进行的 研究的目的不仅是提供机制的见解的作用，关键的信号通路，在 各种骨消耗性疾病的病理生理学，而且还可以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.