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脂质过量影响肺纤维化发展的分子机制。肥胖影响超过三分之一的美国人，是发病率和死亡率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发展中的作用已得到充分研究，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病，预后不良，中位生存期为5年。已经确定了IPF发展的几个风险因素，但其病因仍然不确定，并且没有发现有效的治疗。重要的是，与肥胖症一样，IPF的患病率也在上升。需要了解肥胖如何影响IPF的发生和进展，以确定潜在的重要可改变风险因素和治疗靶点，并最终改善这种毁灭性疾病的结局。拟议的项目将通过专门探索脂质过量调节实验性肺纤维化的机制来解决这一需求。已经开发了一种小鼠模型，其证明高脂肪饮食导致对博来霉素诱导的肺纤维化的易感性增加和死亡率增加。使用这个模型和其他基于细胞的测定，该项目旨在为这些发现建立分子基础。它将研究脂质过量对已知在肺纤维化发展中起关键作用的三种特定机制的影响：TGF-β 1信号传导，NLRP 3炎性小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，并深入了解肥胖（一种高度流行的疾病）如何改变IPF的病程。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，同时她进行拟议的研究。该项目将包括她的研究奖学金的核心，并提供必要的培训，她的发展作为一个医生科学家在肺部疾病领域。预期完成拟定目标将导致进一步发现代谢异常在IPF发生中的作用。她将在布里格姆妇女医院的肺部和重症监护医学部内开展这一项目，并得到她的赞助人伊万罗萨斯博士和共同赞助人伊丽莎白·亨斯克博士的密切指导，以及她的科学咨询委员会其他高度成就的成员的专业知识。她将有机会在她的部门和哈佛生物医学界获得全面的智力和物质资源，从而准备获得成功完成这个项目所需的研究培训，并培养她的学术医学生涯。

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.