Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury

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，旨在为埃默里大学终身医学助理教授Viranuj Sueblinvong博士在酒精和肺部生物学研究方面的学术生涯发展。在K08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，并在实验小鼠模型中研究慢性酒精摄入干扰急性损伤后肺修复的机制。David Guidot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。他指导了许多研究实习生，其中包括四名获得NIH K奖和两名获得VA职业发展奖的教师。他的酒精和肺部研究由美国国立卫生研究院和退伍军人管理局资助，并与该领域的主要研究人员合作。与此同时，一个由埃默里大学（Emory University）高级研究人员组成的指导委员会已经成立，以帮助指导和指导苏布林荣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表明，慢性酒精摄入与急性肺损伤（ALI）的发生率增加有关，这种风险可能是由酒精诱导的氧化应激引起的。然而，酒精对急性脑损伤后的修复和恢复过程的影响尚未得到研究。我们在相关临床前动物模型中的初步数据表明，摄入酒精会干扰博莱霉素诱导ALI后的肺修复。我们有新的证据表明，这一病理生理序列始于Nrf2信号的抑制，Nrf2是激活抗氧化反应元件（ARE）所需的转录因子。因此，关键抗氧化剂硫氧还蛋白-1 （Trx1）的表达被抑制，进一步抑制ARE的激活，因为Trx1的功能之一是稳定Nrf2。与这个序列一致，Nrf2的激活

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. PUBLIC HEALTH RELEVANCE: Recent studies have identified previously unrecognized effects of chronic alcohol ingestion on the lung that can greatly increase the risk of severe lung injury and death even in otherwise healthy-appearing individuals. Experimental data discussed in this application provide novel evidence that chronic alcohol ingestion interferes with normal repair processes in the lung following injury. The proposed studies will investigate the mechanisms by which alcohol interferes with normal repair and can cause chronic lung damage and scarring.