BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10337066
• 负责人: SUBBURAMAN MOHAN
• 金额: --
• 依托单位: VA LOMA LINDA HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10337066
• 关键词: Adult; Adverse effects; Affect; Age; Aging; Area; Ascorbic Acid; Ascorbic Acid Deficiency; Award; Bone Diseases; Bone Marrow; Book Chapters; Cartilage; Clinical; Collaborations; Complement Factor H; Degenerative polyarthritis; Development; Diagnosis; Drug Targeting; Elderly; Elements; Epigenetic Process; Event; Family; Financial Hardship; Fracture; Functional disorder; Funding; Future; General Population; Generations; Genes; Genetic Transcription; Goals; Health; Healthcare; Heterotopic Ossification; Hydroxylation; Hypoxia; Impairment; Injury; International; Knock-out; Laboratories; Lead; Life; Life Style; Mediating; Medical; Mentors; Metabolic Bone Diseases; Metabolism; Minerals; Mission; Molecular; Musculoskeletal; Musculoskeletal Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Obesity; Osteoclasts; Osteogenesis; Osteoporosis; Oxygen; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; Phosphotransferases; Population; Prevention strategy; Process; Procollagen-Proline Dioxygenase; Productivity; Promoter Regions; Proteins; Public Health; Publications; Publishing; Quality of life; Regulation; Research; Research Peer Review; Research Personnel; Research Priority; Role; Scientist; Seminal; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal system; Survivors; TBI Patients; TNFSF11 gene; Tertiary Protein Structure; Therapeutic; Thyroid Hormone Receptor Beta; Tight Junctions; Time; Tissues; Translational Research; Trauma; Traumatic Brain Injury; United States National Institutes of Health; Veterans; Wasting Syndrome; Woman; Work; age related; aged; base; bone; bone cell; bone fracture repair; bone loss; bone mass; bone metabolism; career; chronic pain; combat injury; combat zone; comorbidity; design; diabetic patient; effective therapy; functional status; health care delivery; high risk; hospitalization rates; improved; indexing; insight; meetings; member; men; mild traumatic brain injury; military service; military veteran; mortality; neurotransmission; new therapeutic target; notch protein; novel; novel therapeutic intervention; patient population; physically handicapped; prevent; programs; rehabilitation strategy; response; sensor; service member; skeletal abnormality; soft tissue; treatment strategy

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.

概括 我的 SRCS 计划的这一竞争性更新申请重点关注以下三个主要健康问题： VA 患者群体、TBI、骨质疏松症和骨关节炎是我们关注的主要领域之一。 创伤性脑损伤 (TBI) 对骨骼的负面影响是战斗行动的标志性损伤。 在无数的临床并发症中，这些并发症对我们的战场战士造成毁灭性影响，并代表了一种 在我们的研究中，我们确定了 CRADO 的五个交叉临床重点。 通过影响峰值骨量，对骨骼系统产生长期显着的负面影响 我们目前的研究重点是促进损伤后软组织的异位骨形成。 阐明影响细胞的关键细胞元件以及相关的系统和局部信号通路 针对 TBI 和局部创伤而产生异位骨，目标是开发新的治疗方法 TBI 患者异位骨化的预防和治疗策略。 老年退伍军人人数持续增加，因此影响老年人的问题日益突出 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，并造成巨大的经济负担。 据估计，50 岁及以上的女性中约有二分之一和男性中四分之一的人会因以下原因骨折： 骨质疏松症已知影响美国超过 3000 万成年人。骨质疏松症和 OA 的发病机制 已知会增加骨和软骨的破坏，而不是通过骨和软骨的平行增加来补偿 因此，我的 VA 和 NIH 资助的研究的长期目标集中在新组织的合成上。 识别导致老年人骨和软骨损失的有缺陷的信号通路，并 开发新的合成代谢策略来治疗这些使人衰弱的骨疾病。 我们的实验室多年来一直非常高效，发表了 370 篇同行评审研究文章、30 条评论 我们的出版物已获得超过 45,000 次引用，H 因子为 89。 i-10 指数为 839。我们的研究在骨骼和矿物质领域取得了多项重要发现 新陈代谢，并在 30 年来持续获得联邦机构（VA、NIH、DOD）的资助。 我荣获 2017 年 ASBMR Louis Avioli 创始人奖，该奖项旨在表彰我的终身贡献 除了建立强大的活性外，还从事与骨和矿物质代谢相关的转化研究。 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 研究人员并为 VA 在地方和国家层面的研究管理做出贡献。 研究的目的不仅是提供对关键信号通路在 各种骨消耗疾病的病理生理学，同时也为这些疾病确定新的、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疾病。