Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury

酒精引起的氧化应激会抑制急性肺损伤的恢复

• 批准号: 8541686
• 负责人: VIRANUJ SUEBLINVONG
• 金额: $ 16.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8541686
• 关键词: Acute; Acute Lung Injury; Alcohol abuse; Alcohol consumption; Alcohols; Animal Model; Antioxidants; Attenuated; Automobile Driving; Award; Biology; Bleomycin; Cessation of life; Chronic; Cicatrix; Data; Development; Experimental Models; Faculty; Fibroblasts; Fibrosis; Funding; Glutathione; Goals; Health; Incidence; Individual; Injury; K-Series Research Career Programs; Lead; Lung; Mediating; Medicine; Mentors; Myofibroblast; Nuclear; Oxidative Stress; Physicians; Pilot Projects; Pre-Clinical Model; Process; Program Development; Recovery; Research; Research Personnel; Resolution; Response Elements; Risk; S-Adenosylmethionine; Scheme; Scientist; Seminal; Series; Signal Transduction; Staging; Sulforaphane; Testing; Therapeutic; Thioredoxin; Training Programs; Transforming Growth Factors; Transgenic Organisms; United States National Institutes of Health; Universities; alcohol effect; alcohol use disorder; attenuation; base; career; career development; chronic alcohol ingestion; design; dietary supplements; human subject; improved; lung injury; lung repair; member; mouse model; novel; pre-clinical; problem drinker; professor; programs; repaired; research clinical testing; response; skills; transcription factor; transdifferentiation

DESCRIPTION (provided by applicant): The application describes a 5-year training program for the development of an academic career in Alcohol and Lung Biology research for Dr. Viranuj Sueblinvong, Assistant Professor of Medicine on the tenure track at Emory University. With the support of this K08 Award, she will develop and refine her skills as a biomedical investigator and study the mechanisms by which chronic alcohol ingestion interferes with lung repair following an acute injury in an experimental mouse model. Dr. David Guidot, an internationally-recognized expert in the biology of the 'alcoholic lung', will mentor her scientific and career development. H has mentored many research trainees, including four faculty members supported by NIH K Awards and two by VA Career Development Awards. He is funded for his alcohol and lung research by the NIH and the VA, and collaborates with leading investigators in this field. In parallel, a mentoring committee comprised of senior investigators at Emory University has been formed to help mentor and guide Dr. Sueblinvong's scientific career development. Investigators in the Emory Alcohol and Lung Biology Center have shown that chronic alcohol ingestion is associated with an increased incidence of acute lung injury (ALI), and that this risk is likely driven by alcohol- induced oxidative stress. However, the effects of alcohol on repair and recovery processes following ALI have not been studied. Our preliminary data in a relevant pre-clinical animal model suggest that alcohol ingestion interferes with lung repair following bleomycin-induced ALI. We have novel evidence that this pathophysiological sequence begins with a dampening of signaling by Nrf2, the transcription factor required to activate the anti-oxidant response element (ARE). As a consequence, expression of the critical anti-oxidant thioredoxin-1 (Trx1) is dampened, further inhibiting activation of the ARE as one of the functions of Trx1 is to stabilize Nrf2. Consistent with this proposed sequence, either the activation of Nrf2 with sulforaphane (a naturally-occurring compound that has been shown to activate Nrf2) or the nuclear-specific over-expression of Trx1 would result in the attenuation of transforming growth factor-¿1 (TGF¿1) expression. These results lead us to hypothesize that alcohol disrupts the dynamic interactions between Nrf2 and Trx1 and that the consequent oxidative stress induces the aberrant expression of TGF¿1 which impairs the ability of the lung to repair and recover from injury. The experimental approaches are designed to test this hypothesis, and these studies are expected to provide a scientific basis for the underlying mechanisms by which alcohol interferes with normal repair following ALI. This program of research, together with the collective expertise within Emory University and its focus on nurturing exceptional junior scientists, constitute an ideal setting for a physician-scientist at this critical stage of her carer development to acquire the diverse and specialized skills necessary to become an independent investigator focused on improving the health of individuals suffering from alcohol use disorders.

描述（由申请人提供）：该申请描述了一个为期5年的培训计划，用于埃默里大学终身教职医学助理教授Viranuj Sueblinvong博士在酒精和肺生物学研究方面的学术生涯发展。在这个K 08奖的支持下，她将发展和完善她作为生物医学研究者的技能，并研究慢性酒精摄入干扰实验小鼠模型急性损伤后肺修复的机制。大卫圭多博士是国际公认的“酒精肺”生物学专家，他将指导她的科学和职业发展。H指导了许多研究学员，包括四名由NIH K奖支持的教员和两名由VA职业发展奖支持的教员。他的酒精和肺部研究由NIH和VA资助，并与该领域的主要研究人员合作。与此同时，由埃默里大学高级研究人员组成的指导委员会已经成立，以帮助指导和指导Sueblinvong博士的科学职业发展。埃默里酒精和肺生物学中心的研究人员已经表明，慢性酒精摄入与急性肺损伤（ALI）发生率增加有关，这种风险可能是由酒精诱导的氧化应激引起的。然而，尚未研究酒精对ALI后修复和恢复过程的影响。我们在相关临床前动物模型中的初步数据表明，酒精摄入干扰博莱霉素诱导的ALI后的肺修复。我们有新的证据表明，这一病理生理序列开始于抑制信号传导的Nrf 2，转录因子所需的激活抗氧化反应元件（ARE）。因此，关键的抗氧化剂硫氧还蛋白-1（Trx 1）的表达受到抑制，进一步抑制ARE的激活，因为Trx 1的功能之一是稳定Nrf 2。与此提出的序列一致，Nrf 2的激活 与萝卜硫素（一种天然存在的化合物，已被证明能激活Nrf 2）或Trx 1的核特异性过表达将导致转化生长因子1（TGF 1）表达的减弱。这些结果使我们假设酒精破坏了Nrf 2和Trx 1之间的动态相互作用，并且随后的氧化应激诱导TGF？1的异常表达，从而损害肺修复和从损伤中恢复的能力。实验方法旨在验证这一假设，这些研究有望为酒精干扰ALI后正常修复的潜在机制提供科学依据。这项研究计划，连同埃默里大学的集体专业知识及其对培养杰出的初级科学家的关注，构成了一个理想的环境，为医生科学家在她的照顾者发展的这个关键阶段获得必要的多样化和专业技能成为一个独立的调查员，专注于改善个人的健康患有酒精使用障碍。