Regulation of eicosanoid signaling lipids to improve skeletal muscle function and increase healthspan during aging

摘要 COVID-19症状的严重程度与年龄以及其他合并症（如糖尿病、贫困）直接相关。 呼吸功能和心血管疾病。截至9月22日，约有700万例新冠肺炎病例- 美国报告了19例，整体累计COVID-19住院率很高， 65岁以上的人因COVID-19住院的可能性是40岁以下的人的12倍。而在 在医院，许多COVID-19患者需要呼吸机的呼吸支持。尽管许多患者存活下来， COVID-19，由于膈肌无力，恢复时间延长，有些人从未完全恢复， 呼吸机引起的膈肌功能障碍（VIDD），一种降低患者脱机能力的疾病 独立呼吸。老年COVID-19患者的VIDD风险和严重程度增加， 易受感染，因为他们花了几周，而不是几天，固定和机械通气。 目前还没有治疗VIDD的方法。该项目旨在获取临床前数据以支持治疗 对于VIDD，它利用了一种有前途的新小分子，其作用机制不同于先前测试的机制 开发治疗VIDD的药物。我们的初步数据表明，前列腺素E2（PGE 2）， 我们的药物作用于肌肉干细胞（MuSC）以增强其增殖和再生功能， 对成熟的肌纤维，以提高力量，特别是在老年人。我们假设PGE 2/EP 4信号通路 将像在老年肢体肌肉中一样在老年膈肌中起作用，并且可以调节以改善膈肌 功能具体来说，我们的目标是（i）证明PGE 2增强了增殖和再生功能， 从患者戴上呼吸机后4小时获得的人膈肌活检中分离的MuSC，和（ii） 评估我们的药物在增强MuSC功能和促进肌纤维肥大以对抗 在VIDD的啮齿动物模型中的隔膜萎缩。为了实现这些目标，我们将利用人类膈肌活检 在心胸外科手术时从年轻（<40岁）和老年（> 65岁）患者中获得， 培养中和移植后PGE 2处理的人MuSC再生能力的功能测定 免疫缺陷小鼠。我们还将评估人类膈肌是否由呼吸机引起的快速萎缩 导致PGE 2水平下降和TGF-β、cAMP/CREB和AKT/FOXO信号通路的破坏。 最后，我们将确定通过我们的治疗方法升高PGE 2是否能改善膈肌功能和再生功能。 在一个成熟的VIDD啮齿动物模型中，机械通气的情况下， 隔膜萎缩和收缩力降低。该项目是斯坦福大学 教授，海伦布劳博士，谁的特点是一种新的小分子药物作为一个潜在的治疗肌肉减少症， 约瑟夫·施拉格博士，一位著名的心胸外科医生，他进行了VIDD临床试验。我们的药， 如果被证明有效，可能会使COVID-19患者更早地脱离呼吸机，并显著改善 COVID-19的结果，特别是老年患者。

ABSTRACT COVID-19 symptom severity is directly linked to age as well as other comorbidities such as diabetes, poor respiratory function, and cardiovascular disease. As of September 22, approximately 7.0 million cases of COVID- 19 have been reported in the US, and the overall cumulative COVID-19 hospitalization rate is high, with individuals over age 65 twelve times as likely as those under 40 to be hospitalized for COVID-19. While in the hospital, many COVID-19 patients require respiratory support from a ventilator. Although many patients survive COVID-19, recovery is prolonged due to diaphragm muscle weakness and some never completely recover due to ventilator-induced diaphragm dysfunction (VIDD), a condition that reduces the ability of a patient to be weaned to independent breathing. VIDD risk and severity increase in elderly COVID-19 patients who are particularly susceptible because they spend weeks, as opposed to days, immobilized and on mechanical ventilation. There is currently no treatment for VIDD. This project proposes to acquire preclinical data in support of a therapy for VIDD that utilizes a promising new small molecule that acts by a mechanism different from previously tested therapeutics developed to treat VIDD. Our preliminary data suggest that Prostaglandin E2 (PGE2), the target of our drug, acts on both muscle stem cells (MuSCs) to augment their proliferation and regenerative function, and on mature myofibers to improve strength, particularly in the elderly. We hypothesize that PGE2/EP4 signaling will act in aged diaphragm muscles as in aged limb muscles and can be modulated to improve diaphragm muscle function. Specifically, we aim to (i) demonstrate that PGE2 augments the proliferative and regenerative function of MuSCs isolated from human diaphragm biopsies obtained 4 hr after patients are put on a ventilator and (ii) assess the efficacy of our drug in enhancing MuSC function and promoting myofiber hypertrophy to counter diaphragm atrophy in a rodent model of VIDD. Toward these goals, we will utilize human diaphragm biopsies obtained from young (< 40yr) and elderly (> 65yr) patients at the time of cardiothoracic surgery and perform both functional assays of PGE2 treated human MuSC regenerative capacity in culture and following transplantation into immunodeficient mice. We will also assess in human diaphragm if the rapid atrophy induced by a ventilator leads to a decline in PGE2 levels and disruption of TGF-beta, cAMP/CREB, and AKT/FOXO signaling pathways. Finally, we will determine if PGE2 elevation via our therapeutic improves diaphragm function and regenerative capacity in the context of mechanical ventilation in a well-established rodent model of VIDD, which causes diaphragm atrophy and reduced contractile force. The project is a preclinical collaboration between Stanford faculty, Dr. Helen Blau, who characterized a novel small molecule drug as a potential therapeutic for sarcopenia, and Dr. Joseph Shrager, a prominent cardiothoracic surgeon who has carried out VIDD clinical trials. Our drug, if proven effective, may allow earlier weaning from ventilators of COVID-19 patients and significantly improve COVID-19 outcomes, particularly for elderly patients.