Surfactant Protein C Mutations and Interstitial Lung Disease

特发性肺纤维化（IPF）是一种进行性瘢痕性间质性肺病（ILD），主要影响老年人， 成人仍然是一个显著未满足的治疗需求。最近的范式转变，其中重复的概念， 对功能障碍、脆弱的肺泡上皮的损伤与异常的伤口愈合反应相结合， 作为疾病的“驱动因素”，为IPF的治疗发现开辟了新的机会。超过60种突变 肺泡2型细胞（AT 2）限制性，表面活性蛋白C [SP-C]基因[SFTPC]，已发现在散发性 与家族性IPF的关系，为了解IPF的发病机制提供重要线索。由于其最初的资金超过 10年前，这项绩效审查计划通过利用两个方面解决了IPF退伍军人未满足的需求， 在肺泡型中表达临床SP-C突变体的自发性肺纤维化的新型敲入小鼠模型 3（AT 2）上皮细胞以诱导方式研究IPF。最近一次续约（2021年）获得3%ile评分 并获得了8年的资助，作为高级临床科学家研究者奖，直到2029年。这个项目 旨在interrogate细胞质量控制和综合应激反应，以确定关键的肺泡生态位细胞 在纤维化过程中出现的群体，然后评估内源性内质网（ER）的作用 压力和AT 2代谢重编程在IPF异常损伤/修复途径中的作用。利用这一成功 和稳定的基础设施，该补充是响应VA RFA RD-22-029，其设计将扩展 范围的母公司的优点审查，以及促进多样性，通过支持职业发展的一个 杰出的早期研究员从一个代表性不足的少数民族（路易斯罗德里格斯，博士）。具体 目的是检验细胞质量控制缺陷（宏自噬;蛋白酶体） 破坏AT 2代谢并与衰老协同作用，破坏AT 2祖细胞功能并加速衰老 导致在远端肺中出现促纤维化小生境。科学和技术可行性的支持， Rodriguez博士收集的新的初步数据显示：（i）表达突变SPC的老年小鼠 （ii）老年小鼠中的AT 2细胞存在增加的 细胞衰老（iii）老年小鼠具有增加的AT 2移行细胞的患病率，和（iv）AT 2 移行细胞表现出增加的代谢功能障碍。所设想的实验方法将 表征与肺纤维化相关的多个中断途径之间的协同作用。目标1a 将使用多西环素诱导的SftpcI 73 T鼠上皮细胞系来评价衰老对细胞周期的影响。 AT 2细胞代谢。目的2利用老年（>18月龄）SftpcI 73 T IPF小鼠的可用性， 确定衰老和AT 2代谢重编程对衰老和祖细胞功能的影响（以及 反之亦然）。我们的方法同时使用简化和综合模型，并提供了独特的机会， 全面识别促进AT 2细胞、炎性细胞和细胞间串扰的机制和途径 以及驱动实质重塑的成纤维细胞。虽然本补编所取得的成果将提供 对森林小组领域的重大科学影响，同样重要的是其对实现 通过提供关键基础设施，促进VA生物医学研究人员的多样性， 数据和指导，以支持拟议学员职业发展的下一步， 成功竞争一个VA CDA。

Idiopathic pulmonary fibrosis (IPF) a progressive scarring interstitial lung disease (ILD) that affects mainly older adults remains a significant unmet therapeutic need. The recent paradigm shift wherein the concepts of repetitive injury to a dysfunctional, vulnerable, alveolar epithelium coupled with an abnormal wound healing response serve as disease “drivers” is opening up new opportunities for therapeutic discovery in IPF. Over 60 mutations in the alveolar type 2 cell (AT2) restricted, Surfactant Protein C [SP-C] gene [SFTPC], have been found in sporadic and familial IPF and provide important clues for understanding IPF pathogenesis. Since its initial funding over 10 years ago, this Merit Review program has addressed the unmet need for veterans with IPF by leveraging two novel knock-in mouse models of spontaneous lung fibrosis which express clinical SP-C mutants in alveolar type 3 (AT2) epithelial cells in an inducible fashion to study IPF. The latest renewal (2021) received a 3%ile score and was awarded 8 years of funding as a Senior Clinician Scientist Investigator Award through 2029. This project is designed to interogate cell quality control and integrated stress responses to define key alveolar niche cell populations emerging during fibrogenesis and then assess the roles of endogenous endoplasmic reticulum (ER) stress and AT2 metabolic reprogramming in aberrant injury/repair pathways found in IPF. Using this successful and stable infrastructure, this supplement is responsive to VA RFA RD-22-029 in that its design will extend the scope of the parent Merit Review as well as promote diversity through support of the career development of an outstanding early stage investigator from an under-represented minority (Luis Rodriguez, PhD). The specific aims are designed to test the hypothesis that defects to cell quality control (macroautophagy; proteasome) disrupt AT2 metabolism and synergize with aging to disrupt AT2 progenitor function and accelerate senescence resulting in emergence of a pro-fibrotic niche in the distal lung. Scientific and technical feasibility is supported by the new preliminary data collected by Dr. Rodriguez that show: (i) Aged mice expressing mutant SPC have increased mortality as compared to younger mice (ii) AT2 cells in aged mice present with increased markers of cellular senescence (iii) Aged mice have an increased prevalence of AT2 transitional cells and (iv) AT2 transitional cells demonstrate increased metabolic dysfunction. The contemplated experimental approach will characterize synergism between multiple disrupted pathways associated with pulmonary fibrosis. In Aim 1 a doxycycline inducible SftpcI73T murine epithelial cell line will be used to evaluate the impact of senescence on AT2 cellular metabolism. Aim 2 leverages the availability of aged (>18-month-old) SftpcI73T IPF mice to determine the impact of aging and AT2 metabolic reprogramming on senescence and progenitor function (and vice versa). Our approach uses both reductionist and integrative models and offers the unique opportunity to comprehensively identify mechanisms and pathways promoting crosstalk between AT2 cells, inflammatory cells and fibroblasts that drive parenchymal remodeling. While the results achieved in this supplement will provide significant scientific impact to the field of IPF, of equal value will be its contribution towards achieving the objective of advancing diversity in the VA biomedical research workforce by providing critical infrastructure, data, and mentoring to support the next steps in career development of the proposed mentee punctuated by successful competition for a VA CDA.