Alcohol Induced Oxidative Stress Inhibits Recovery From Acute Lung Injury

描述(由申请者提供)：申请书描述了为埃默里大学终身医学助理教授Viranuj Sueblinvong博士提供的为期5年的酒精和肺生物学研究学术生涯发展培训计划。在K08奖的支持下，她将发展和完善她作为生物医学研究人员的技能，并研究在实验性小鼠急性损伤后长期饮酒干扰肺修复的机制。大卫·吉多博士是国际公认的酒精性肺生物学专家，她将指导她的科学和职业发展。H指导了许多研究实习生，其中包括四名获得NIH K奖支持的教职员工和两名获得退伍军人管理局职业发展奖支持的教职员工。他的酒精和肺部研究得到了美国国立卫生研究院和退伍军人管理局的资助，并与该领域的领先调查人员合作。与此同时，一个由埃默里大学高级研究人员组成的指导委员会已经成立，以帮助指导和指导苏布林松博士的科学事业发展。埃默里酒精和肺生物学中心的研究人员已经表明，长期饮酒与急性肺损伤(ALI)的发病率增加有关，而且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ALI后修复和恢复过程的影响尚未被研究。我们在相关的临床前动物模型中的初步数据表明，酒精摄入干扰了博莱霉素诱导的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，关键的抗氧化剂硫氧还蛋白-1(Trx1)的表达受到抑制，进一步抑制ARE的激活，因为Trx1的功能之一是稳定Nrf2。与这一建议的序列一致，Nrf2的激活 用萝卜硫素(一种天然化合物，已被证明激活Nrf2)或核特异性Trx1的过度表达会导致转化生长因子-1(TGF？1)的表达减弱。这些结果使我们假设酒精破坏了Nrf2和Trx1之间的动态相互作用，随后的氧化应激诱导了转化生长因子β1的异常表达，从而削弱了肺修复和恢复损伤的能力。实验方法旨在验证这一假说，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基础。这一研究计划，再加上埃默里大学的集体专业知识及其对培养杰出初级科学家的关注，构成了一个理想的环境，使处于护理发展关键阶段的内科科学家获得必要的多样化和专门技能，成为专注于改善酒精使用障碍患者健康的独立调查员。

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.