BLR&D Research Career Scientist Award Application (Renewal)

项目摘要/摘要 我的RCS计划的这一竞争性续订申请专注于视力的一个主要健康问题 因眼外伤和脑损伤造成的损失。眼和脑创伤都会导致视力丧失和 眼组织损伤，极大地影响退伍军人的健康和生活质量。眼部和脑部创伤是 我们的退伍军人和参与持久自由行动(OEF)的部队中视力丧失的主要原因， 伊拉克自由行动(OIF)、新黎明和打击恐怖主义。尽管使用了防护装备，但眼睛受伤 从世界大战的2%上升到OIF和OEF的13%。目前，有167,000名退伍军人合法失明，其中1.5人 每年有100万人视力严重受损，7000名退伍军人失明。两者都是创伤 眼睛和脑损伤在退伍军人、现役军人和平民中变得越来越常见。 此外，老年退伍军人的人口不断增加，因此开发了新的分子 治疗已成为退伍军人管理局研究任务的重要优先事项。 我们的研究重点是研究外伤性眼和脑损伤对视力丧失的影响。我们的 项目的重点是开发治疗角膜的新型纳米药物和基于基因的疗法。 纤维化/瘢痕形成，揭示导致角膜损伤的病理生理机制，并促进 角膜伤口愈合和糖尿病视网膜病变的机制理解。我们的长远目标是 研究旨在建立新的有效和安全的分子疗法来治疗失明和恢复视力 人类和服务犬。我们正在实施四个具体项目，以实现我们的近期和长期目标。 项目-1确定了外伤性眼睛和脑损伤如何导致严重的眼睛缺陷和失明 并通过评估化学/手术损伤对视力丧失的影响来随时间发散。项目2阐明了 表观遗传机制和信号通路在角膜纤维化发病机制中的作用 或结疤)和其他眼部疾病。Project-3旨在开发新的纳米医学和基因疗法 利用已建立的人体外治疗角膜纤维化/混浊和恢复视力的方法 器官培养和体内动物(兔、猪和啮齿动物)模型，模拟在 人类病人。项目-4的重点是研究与化学毒性和 开发多种形式的局部滴眼液，以减轻战争和 有毒化学品、硫磺芥末、丙烯醛、氯和硫化氢。 我们的实验室在目前的RCS资助期间非常有成效，多年来已经有140+ 同行评议期刊研究文章，350多篇科学报告，10个书籍章节，47个邀请 杰出的演讲者在包括哈佛医学院和全球科学学院在内的著名机构发表演讲 会议包括世界眼科大会，ARVO，欧洲视力和眼科研究， 国际眼科学会、亚太眼科科学院、精准医学等 目前的RCS周期，我已经在英国、法国、意大利、亚洲、加拿大、南非、 美国等，共有44个享有盛誉的荣誉和奖项授予我和我的学员。另外，我们的 研究已经收到了8,200条引文，其中H因子为48，I-10指数为98(&gt；3000条 当前RCS周期)。我们的眼睛翻译研究在以下领域有了几个重要的发现 角膜基因治疗、纳米医学、伤口愈合和糖尿病视网膜病变，并已连续收到 资金来自联邦(退伍军人事务部和国家卫生研究院)和非联邦(基金会、行业等)代理的价格超过4000万美元。我们的 正在进行的研究具有高度的翻译性，旨在确定新的治疗靶点，提供 对关键信号通路在角膜疾病病理生理学中的作用的机械论见解， 并导致开发有效的疗法来治疗影响退伍军人健康的失明。

Project Summary/Abstract This competitive renewal application of my RCS program is focused on a major health problem of vision loss caused by the traumatic eye and brain injury. Both, traumatic eye and brain injuries lead to vision loss and ocular tissue damage that affects veterans’ health and quality of life immensely. Eye and brain trauma are the major cause of vision loss among our veterans and troops engaged in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), New Dawn, and fighting terrorism. Despite using protective gears, eye injuries has risen from 2% in World Wars to 13% in OIF and OEF. Presently, >167,000 Veterans are legally blind, 1.5 million have significantly compromised vision, and >7000 veterans becoming blind each year. Both, traumatic eye and brain injuries are becoming more common among Veterans, active military personnel, and civilians. Also, the population of elderly Veterans continues to increase, and therefore development of novel molecular therapies has become a vital priority of VA research mission. Our research is focused on studying the impact of traumatic eye and brain injuries on vision loss. Our projects are focused towards developing novel nanomedicine and gene-based therapies for treating corneal fibrosis/scarring, uncovering pathophysiologic mechanisms leading to corneal damage, and advancing the mechanistic understanding of corneal wound healing and diabetic retinopathy. The long-range goal of our research is to establish novel efficacious and safe molecular therapies to treat blindness and restore vision in humans and service dogs. We are pursuing four specific projects to achieve our immediate and long-range goals. Project-1 establishes how traumatic eye and brain injuries lead to significant eye defects and blindness acutely and transpire over time by evaluating the impact of chemical/surgical injury on vision loss. Project-2 elucidates the role of epigenetic mechanisms and signaling pathways in the pathogenesis of corneal fibrosis (also called haze or scarring) and other ocular disorders. Project-3 aims to develop novel nanomedicine and gene therapy approaches for treating corneal fibrosis/opacity and restoring vision using established human in vitro, human organ culture, and in vivo animal (rabbit, pig and rodent) models that mimic pathological conditions seen in human patients. Project-4 is focused on studying the pathogenesis processes linked to chemical toxicity and developing multimodal topical ophthalmic drops to mitigate acute and chronic toxicity caused by warfare and toxic chemicals, sulfur mustard, acrolein, chlorine, and hydrogen sulfide. Our laboratory has been very productive during the current RCS funding, and over the years with 140+ peer review journal research articles, 350+ scientific presentations, 10 book chapters, and 47 invited distinguished speaker talks at prestigious institutions including the Harvard Medical School and global scientific meetings including the World Ophthalmology Congress, ARVO, European Vision and Eye Research, International Society for Eye Research, Asia-Pacific Academy of Ophthalmology, Precision Medicine etc. In present RCS cycle, I have delivered 27 international invited talks in UK, France, Italy, Asia, Canada, South Africa, USA etc. and collectively 44 prestigious honors and awards were conferred to my trainees and me. Also, our research has received >8,200 citations with an H-factor of 48 and an i-10-index of 98 (>3000 citations during current RCS cycle). Our eye translational research has led to several important discoveries in the areas of corneal gene therapy, nanomedicine, wound healing, and diabetic retinopathy and has received continuous funding from federal (VA and NIH) and non-federal (foundations, industry etc.) agencies for over $40 million. Our ongoing studies are highly translational and are designed to identify novel therapeutic targets, provide mechanistic insights into the role of the key signaling pathways in the pathophysiology of the corneal diseases, and lead to the development of effective therapies to treat blindness that impact the health of veterans.