BLR&D Research Career Scientist Award Application (Renewal)

BLR

• 批准号: 10373048
• 负责人: Rajiv Ravindra Mohan
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10373048
• 关键词: Academy; Acrolein; Acute; Affect; Americas; Animal Model; Animals; Area; Asia; Automobile Driving; Award; Bilateral; Blindness; Book Chapters; Brain Injuries; Canada; Canis familiaris; Chemical Injury; Chemicals; Chlorine; Chronic; Cicatrix; Complement Factor H; Congresses; Cornea; Corneal Diseases; Corneal Neovascularization; Corneal dystrophy; Data; Defect; Dependovirus; Development; Diabetic Retinopathy; Disabled Persons; Disease; Drops; Elderly; Ensure; Epigenetic Process; European; Event; Eye; Eye Enucleation; Eye Injuries; Family suidae; Fibrosis; Formulation; Foundations; France; Freedom; Functional disorder; Funding; General Population; Genes; Goals; Grant; Health; Human; Hydrogen Sulfide; In Vitro; Industry; Injury; Institution; International; Interruption; Italy; Journals; Keratoplasty; Koreans; Laboratories; Lasers; Law Enforcement; Lead; Lentivirus; Link; Mediating; Military Personnel; Mission; Modification; Molecular; Mustard Gas; Myopia; Ophthalmologic Surgical Procedures; Ophthalmology; Organ Culture Techniques; Oryctolagus cuniculus; Pathogenesis; Pathologic; Patients; Peer Review; Persons; Photorefractive Keratectomy; Pilot Projects; Plasmids; Poison; Population; Process; Publications; Publishing; Quality of life; Refractive Errors; Research; Retina; Rodent Model; Role; Safety; Scientist; Security; Services; Signal Pathway; Societies; South Africa; Surgical Injuries; Techniques; Terrorism; Testing; Time; Tissues; Toxic effect; Translational Research; Trauma; Traumatic Brain Injury; United States Department of Veterans Affairs; United States National Institutes of Health; Veterans; Vietnam; Vision; War; active duty; base; blind; career; corneal epithelial wound healing; corneal scar; delivery vehicle; design; disability; effective therapy; fighting; gene therapy; health care delivery; health care quality; high risk; in vivo; indexing; injured; insight; legally blind; medical countermeasure; medical schools; meetings; minimally invasive; multimodality; nanomedicine; nanoparticle; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; operation; porcine model; pre-clinical; precision medicine; prevent; programs; response; side effect; sight restoration; therapeutic gene; therapeutic target; vector; wound healing

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.

项目概要/摘要 我的 RCS 计划的这一竞争性更新申请重点关注视力的主要健康问题 外伤性眼部和脑部损伤造成的损失 外伤性眼部和脑部损伤都会导致视力丧失和视力丧失。 眼部组织损伤极大地影响了退伍军人的健康和生活质量。 参与持久自由行动（OEF）的退伍军人和部队视力丧失的主要原因， 伊拉克自由行动（OIF）、新黎明行动和反恐行动尽管使用了防护装备，眼睛还是受伤了。 从世界大战期间的 2% 上升到 OIF 和 OEF 的 13% 目前，超过 167,000 名退伍军人在法律上失明，即 1.5。 数百万人的视力严重受损，每年有超过 7000 名退伍军人失明，这两种情况都造成了创伤。 眼部和脑部损伤在退伍军人、现役军人和平民中越来越常见。 此外，老年退伍军人的数量持续增加，因此新型分子的开发 治疗已成为 VA 研究任务的重中之重。 我们的研究重点是研究外伤性眼部和脑部损伤对视力丧失的影响。 项目的重点是开发用于治疗角膜的新型纳米医学和基因疗法 纤维化/疤痕，揭示导致角膜损伤的病理生理机制，并推进 对角膜伤口愈合和糖尿病视网膜病变的机制的理解是我们的长期目标。 研究目的是建立新型有效且安全的分子疗法来治疗失明和恢复视力 我们正在开展四个具体项目来实现我们的近期和长期目标。 Project-1 确定外伤性眼部和脑部损伤如何导致严重的眼部缺陷和失明 Project-2 通过评估化学/手术损伤对视力丧失的影响，随着时间的推移而发生变化。 表观遗传机制和信号通路在角膜纤维化（也称为雾霾）发病机制中的作用 Project-3 旨在开发新型纳米医学和基因疗法。 使用已建立的体外、人类治疗角膜纤维化/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，模拟病理条件 Project-4 专注于研究与化学毒性和相关的发病机制。 开发多模式局部滴眼剂以减轻战争和战争造成的急性和慢性毒性 有毒化学品、硫芥、丙烯醛、氯和硫化氢。 在目前的 RCS 资助期间，我们的实验室一直非常富有成效，多年来已与 140 多个 同行评审期刊研究文章、350 多篇科学演讲、10 个书籍章节和 47 个受邀文章 哈佛医学院和全球科学学院等著名机构的杰出演讲者 会议包括世界眼科大会、ARVO、欧洲视觉和眼科研究、 国际眼科研究会、亚太眼科学会、精准医学等 目前 RCS 周期中，我已在英国、法国、意大利、亚洲、加拿大、南非等地发表了 27 场国际邀请演讲， 美国等总共 44 项享有盛誉的荣誉和奖项被授予我和我的学员。 研究已获得超过 8,200 次引用，H 因子为 48，i-10 指数为 98（期间超过 3000 次引用） 当前的 RCS 周期）。我们的眼睛转化研究在以下领域取得了多项重要发现： 角膜基因治疗、纳米医学、伤口愈合和糖尿病视网膜病变，并已连续接受 来自联邦（VA 和 NIH）和非联邦（基金会、行业等）机构的资助超过 4000 万美元。 正在进行的研究具有高度转化性，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制见解， 并导致开发有效的疗法来治疗影响退伍军人健康的失明。