The Role of Lipid Excess in Experimental Pulmonary Fibrosis

描述（由申请人提供）：本提案的目的是确定肥胖相关的脂质过剩影响肺纤维化发展的分子机制。肥胖影响着超过三分之一的美国人，是导致发病和死亡的主要可预防原因之一。它在糖尿病、心血管疾病和多种其他疾病的发展中的作用已被充分研究，但对特发性肺纤维化（IPF）的影响知之甚少。IPF是最常见的特发性间质性肺疾病，预后较差，中位生存期为5年。IPF发展的几个危险因素已经确定，但其病因仍不确定，也没有发现有效的治疗方法。重要的是，与肥胖一样，IPF的患病率也在上升。有必要了解肥胖如何影响IPF的发展和进展，以确定潜在重要的可改变的危险因素和治疗靶点，并最终改善这种毁灭性疾病的预后。拟议的项目将通过专门探索脂质过剩可以调节实验性肺纤维化的机制来解决这一需求。一个小鼠模型已经被开发出来，该模型表明高脂肪饮食会增加对博莱霉素诱导的肺纤维化和死亡率的易感性。利用该模型和其他基于细胞的分析，该项目旨在为这些发现建立分子基础。本研究将探讨脂质过剩对三种已知在肺纤维化发展中起关键作用的特定机制的影响：TGF-¿1信号传导、NLRP3炎性体激活和线粒体氧化应激。通过确定脂质过量是否以及如何调节肺纤维化的这些关键效应物，这项工作将揭示潜在的治疗靶点，并为肥胖（一种非常普遍的疾病）如何改变IPF的过程提供见解。因此，该项目有可能对指规数的管理产生重大影响。NRSA将为候选人Sarah Chu博士提供两年的支持，在她进行拟议的研究期间。该项目将构成她研究奖学金的核心，并为她发展成为肺病领域的内科科学家提供必要的培训。上述目标的完成有望导致有关代谢异常在IPF发展中的作用的进一步发现。她将在Brigham and Women’s Hospital的肺科和重症医学科承担这个项目，在她的赞助人Ivan Rosas博士和共同赞助人Elizabeth Henske博士的密切指导下，并在她的科学顾问委员会其他非常有成就的成员的专业知识下。她将有机会获得她所在部门和哈佛生物医学界提供的全面的智力和体力资源，从而准备好获得成功完成该项目所需的研究培训，并培养她在学术医学领域的职业生涯。

DESCRIPTION (provided by applicant): The goal of this proposal is to determine the molecular mechanisms by which obesity-related lipid excess can affect the development of pulmonary fibrosis. Obesity affects over a third of Americans and is one of the leading preventable causes of morbidity and mortality. Its role in the development of diabetes, cardiovascular disease and multiple other diseases has been well-studied, yet little is known about the impact on idiopathic pulmonary fibrosis (IPF). IPF is the most common idiopathic interstitial lung disease and has a poor prognosis with a median survival of 5 years. Several risk factors for the development of IPF have been identified, yet its etiology remains uncertain and no therapy has been found effective. Importantly, the prevalence of IPF, like that of obesity, is rising. There is a need to understand how obesity influences the development and progression of IPF in order to identify potentially important modifiable risk factors and therapeutic targets ad ultimately improve outcomes for this devastating disease. The proposed project will address this need by specifically exploring mechanisms by which lipid excess can modulate experimental pulmonary fibrosis. A mouse model has been developed which demonstrates that high fat diet leads to increased susceptibility to bleomycin-induced pulmonary fibrosis and mortality. Using this model and other cell-based assays, this project aims to establish a molecular basis for these findings. It will investigate the effect of lipid excess on three specific mechanisms that ar known to play critical roles in the development of lung fibrosis: TGF-¿1 signaling, NLRP3 inflammasome activation and mitochondrial oxidative stress. By determining if and how lipid excess modulates these key effectors of pulmonary fibrosis, this work will uncover potential targets for therapy and offer insight into how obesity, a highly prevalent condition, could modify the course of IPF. As such, the project has the potential to significantly impact the management of IPF. The NRSA will provide two years of support for the candidate, Dr. Sarah Chu, while she conducts the proposed research. This project will comprise the core of her research fellowship and provide the training necessary for her development as a physician scientist in the field of pulmonary disease. Completion of the proposed aims is expected to lead to further discoveries pertaining to the role of metabolic abnormalities in the development of IPF. She will undertake this project within the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital, under the close mentorship of her sponsor, Dr. Ivan Rosas and co-sponsor, Dr. Elizabeth Henske, and with the expertise of other highly accomplished members of her scientific advisory committee. She will have access to the comprehensive intellectual and physical resources available within her division and the Harvard biomedical community, thus being poised to obtain the research training required to successfully complete this project and nurture her career in academic medicine.