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

调节类二十烷酸信号脂质以改善骨骼肌功能并延长衰老过程中的健康寿命

• 批准号: 10272407
• 负责人: Helen M Blau
• 金额: $ 59.72万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10272407
• 关键词: Activities of Daily Living; Affect; Age; Aging; Atrophic; Attenuated; Biological Assay; Biopsy; Breathing; COVID-19; COVID-19 diagnosis; COVID-19 mortality; COVID-19 patient; COVID-19 treatment; COVID-19 vaccine; CREB1 gene; Cardiovascular Diseases; Clinical Trials; Collaborations; Contracts; Coupled; Cyclic AMP; Data; Diabetes Mellitus; Dinoprostone; EP4 receptor; Eicosanoids; Elderly; Enzymes; Faculty; Functional disorder; Goals; Homeostasis; Hospitalization; Hospitals; Human; Hypertrophy; Immobilization; Immunodeficient Mouse; Individual; Inflammation Mediators; Limb structure; Link; Lipids; Mechanical ventilation; Mediating; Modeling; Mus; Muscle; Muscle Weakness; Muscle function; Muscle satellite cell; Muscular Atrophy; Mutate; Operative Surgical Procedures; Outcome; Oxidoreductase; Patients; Pharmaceutical Preparations; Pneumonia; Preparation; Proto-Oncogene Proteins c-akt; Rattus; Recovery; Regenerative capacity; Regulation; Reporting; Respiratory Diaphragm; Respiratory physiology; Risk; Rodent; Rodent Model; Role; SARS-CoV-2 infection; Sampling; Severities; Signal Pathway; Signal Transduction; Skeletal Muscle; Surgeon; Symptoms; Testing; Therapeutic; Time; Transforming Growth Factor beta; Transplantation; United States; Ventilator; Ventilator Weaning; WFDC2 gene; Weaning; age group; age-related muscle loss; aged; clinically relevant; comorbidity; effective therapy; experience; healthspan; high risk; hospitalization rates; human old age (65+); improved; inhibitor/antagonist; mortality; muscle aging; muscle strength; novel; older patient; pandemic disease; parent grant; pre-clinical; pre-clinical research; receptor; regeneration function; repaired; respiratory; sarcopenia; severe COVID-19; skeletal muscle wasting; small molecule; stem cell function; stem cell proliferation; stem cell self renewal; stem cells; therapeutic development; therapeutic evaluation

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.

抽象的 COVID-19症状严重程度与年龄以及其他合并症（例如糖尿病）直接相关 呼吸功能和心血管疾病。截至9月22日，大约有700万案 在美国有19个报道，总体累积Covid-19 19也很高，其中 65岁以上的人与40岁以下的年龄相同，即在19岁以下的40岁以下。在 医院，许多Covid-19患者需要呼吸机的呼吸道支持。尽管许多患者幸存 COVID-19，由于diaphragm肌肉无力而延长恢复，有些从未完全恢复 呼吸机诱导的隔膜功能障碍（VIDD），这种疾病可降低患者断奶的能力 独立呼吸。 VIDD的风险和严重程度的增加，年龄在199名患者中的风险和严重程度 易感性，因为他们花了数周的时间，而不是几天，固定并进行机械通气。 目前尚未对Vidd进行治疗。该项目建议获取临床前数据以支持治疗 对于利用有希望的新的小分子的Vidd，该分子由与先前测试的机制不同 为治疗Vidd而开发的治疗剂。我们的初步数据表明，前列腺素E2（PGE2），是 我们的药物作用于两个肌肉干细胞（MUSC），以增加其增殖和再生功能，并且 在成熟的肌纤维上可以提高力量，尤其是在老年人中。我们假设PGE2/EP4信号传导 将在老年肌肉中起作用，如衰老的肢体肌肉，可以调节以改善diaphragm肌肉 功能。具体而言，我们的目的是（i）证明PGE2增强了增殖和再生功能 将患者置于呼吸机和（ii）后，从人隔膜活检中分离出4小时的MUSC 评估我们药物在增强MUSC功能和促进肌纤维肥大中的功效 Vidd啮齿动物模型中的膜片萎缩。朝向这些目标，我们将利用人类隔膜活检 在心胸外科手术时从Young（<40岁）和老年人（> 65岁）患者获得并进行 PGE2治疗的人类MUSC再生能力的功能测定和移植后的功能测定 进入免疫缺陷的小鼠。我们还将在人隔膜中评估是否是由呼吸机诱导的快速萎缩 导致PGE2水平下降以及TGF-beta，CAMP/CREB和AKT/FOXO信号通路的破坏。 最后，我们将确定PGE2升高是否通过我们的治疗方法提高了隔膜功能和再生 在建立良好的啮齿动物模型中机械通气的背景下的能力，这导致了 隔膜萎缩和减少收缩力。该项目是斯坦福大学之间的临床前合作 教师海伦·布劳（Helen Blau）博士将一种新型的小分子药物描述为肌肉减少症的潜在治疗方法 约瑟夫·什拉格（Joseph Shrager）博士是一位著名的心胸外科医生，他进行了VIDD临床试验。我们的药物， 如果被证明有效，则可以允许早期从199例患者的呼吸机中进行断奶，并显着改善 COVID-19的结果，特别是对于老年患者。