The Role of Lipid Excess in Experimental Pulmonary Fibrosis

脂质过多在实验性肺纤维化中的作用

• 批准号: 8783327
• 负责人: Sarah Grace Chu
• 金额: $ 6.16万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-17 至 2016-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783327
• 关键词: A Mouse; Abbreviations; Address; Adipose tissue; Advisory Committees; Affect; Alveolar; American; Antioxidants; Apoptosis; Attenuated; Biological Assay; Bleomycin; Body mass index; Bone Marrow; Bronchoalveolar Lavage; Cardiac; Cardiovascular Diseases; Cells; Cessation of life; Collagen; Communities; Critical Care; Deposition; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Epithelial Cells; Etiology; Fatty Acids; Fatty acid glycerol esters; Fellowship; Fibroblasts; Fibrosis; Functional disorder; Goals; Hamman-Rich syndrome; Hepatocyte; Hospitals; Immune; Immune response; Inflammation; Injury; Insulin Resistance; Interstitial Lung Diseases; Knock-out; Lead; Lipids; Liver; Lung; Lung diseases; Mediating; Medicine; Mentorship; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle Cells; National Research Service Awards; Nonesterified Fatty Acids; Obesity; Outcome; Oxidative Stress; Pancreas; Pathogenesis; Physicians; Play; Predisposition; Prevalence; Production; Publishing; Pulmonary Fibrosis; Reactive Oxygen Species; Research; Research Training; Resources; Risk Factors; Role; Scientist; Signal Transduction; Site; Smoker; Staging; Tissues; Tobacco; Training; United States; Woman; Work; base; body system; career; cytotoxic; effective therapy; feeding; improved; insight; interstitial; lung development; lung injury; macrophage; member; mitochondrial dysfunction; modifiable risk; mortality; mouse model; non-alcoholic; outcome forecast; public health relevance; repaired; therapeutic target

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.

描述(由申请人提供)：本提案的目标是确定肥胖相关的脂质过多影响肺纤维化发展的分子机制。肥胖影响了超过三分之一的美国人，是导致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的发生发展中的作用已被充分研究，但对其对特发性肺纤维化(IPF)的影响却知之甚少。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。目前已经确定了IPF发生的几个危险因素，但其病因仍不确定，也没有发现有效的治疗方法。重要的是，与肥胖症一样，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，以便确定潜在的重要、可改变的危险因素和治疗目标，并最终改善这种毁灭性疾病的预后。拟议的项目将通过具体探索脂质过剩调节实验性肺纤维化的机制来满足这一需求。已经建立了一种小鼠模型，该模型表明高脂饮食会增加博莱霉素性肺纤维化的易感性和死亡率。利用这一模型和其他基于细胞的分析，该项目旨在为这些发现建立一个分子基础。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个特定机制的影响：转化生长因子-β1信号转导、NLRP3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这些肺纤维化的关键影响因素，这项工作将揭示潜在的治疗靶点，并为肥胖这一高度流行的疾病如何改变IPF的病程提供洞察。因此，该项目有可能对森林小组的管理产生重大影响。NRSA将为候选人朱博士提供两年的支持，同时她将进行拟议的研究。该项目将构成她研究奖学金的核心，并为她作为肺部疾病领域的内科科学家的发展提供必要的培训。拟议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，以及她的科学咨询委员会中其他非常有成就的成员的专业知识的指导下，在布里格姆和妇女医院的肺和危重护理医学部内承担这一项目。她将获得她所在部门和哈佛生物医学界提供的全面的智力和物质资源，从而准备好获得成功完成这一项目所需的研究培训，并在学术医学领域培养她的职业生涯。