2-HOBA for Treatment of Pulmonary Hypertension

2-HOBA 治疗肺动脉高压

• 批准号: 10257863
• 负责人: John A Rathmacher
• 金额: $ 25.66万
• 依托单位: MTI BIOTECH, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257863
• 关键词: Acetylation; Address; Affinity; Animal Model; Animals; BMPR2 gene; Binding; Biological Markers; Biopsy; Blood; Blood Vessels; Cells; Cessation of life; Clinical Trials; Data; Deacetylase; Defect; Disease; Disease Progression; Doxycycline; EFRAC; Effectiveness; Etiology; Event; Failure; Genetic; Glucose; Glutamine; Heart; Heart failure; Heritability; Human; Hypoxia; Incidence; Insulin; Intervention; Life; Lipids; Literature; Lung; Lysine; Measurable; Metabolic; Metabolic Marker; Metabolism; Metformin; Methods; Mitochondria; Modeling; Modification; Molecular; Mus; Mutant Strains Mice; Mutation; Nature; Oxygen; Patients; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Prevention; Process; Proteins; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary vessels; Rare Diseases; Reactive Oxygen Species; SOD2 gene; Safety; Sampling; Serum; Testing; Time; Vasodilator Agents; Work; adduct; blood vessel occlusion; circulating biomarkers; disease-causing mutation; early detection biomarkers; efficacy testing; fatty acid oxidation; human disease; in vivo; innovation; molecular phenotype; mouse model; mutant; overexpression; preservation; primary pulmonary hypertension; response; safety testing; small molecule; success; uptake

PROJECT SUMMARY Although the ubiquity of metabolic problems in pulmonary hypertension (PH) has been known for more than a decade, a wealth of new details on the nature of this problem presents the opportunity for intervention. A combination of experimental work in cells and animals and early trials in humans, suggests that these metabolic problems are part of the causation for PH, and that inactivation of the mitochondrial lysine deacetylase SIRT3 is a central node in regulating the metabolic defects. A vicious cycle exists in which a triggering event or mutation increases reactive oxygen species (ROS), which produces reactive lipids, which adduct and inactivate SIRT3, causing metabolic changes that result in further increased ROS. Here, we break this cycle using 2-HOBA, a small molecule which can effectively soak up reactive lipids in vivo and has positive results in safety trials for other indications in humans, with some still ongoing. Effectiveness of 2-HOBA has already been established for the prevention of PH in mice, and the mechanism suggests it should be effective for reversal. Here, we prepare for human trials of 2-HOBA by testing its efficacy for reversal of established disease in two molecularly accurate mouse models alone or in combination with metformin, and by examining serum biomarkers of disease shared between humans and mice for early indications of response which can be used to guide human trials.

项目摘要 尽管肺动脉高压（PH）中普遍存在的代谢问题已经被认为是一个多世纪以来的问题， 十年来，关于这一问题性质的大量新的细节提供了干预的机会。一 结合细胞和动物的实验工作以及人类的早期试验，表明这些 代谢问题是PH的部分原因，线粒体赖氨酸的失活 脱乙酰酶SIRT 3是调节代谢缺陷的中心节点。这是一个恶性循环， 触发事件或突变增加活性氧（ROS），产生活性脂质， 加合物和CSIRT 3，引起代谢变化，导致进一步增加的ROS。在这里，我们打破 该循环使用2-HOBA，其是一种小分子，可以有效地吸收体内的反应性脂质，并且具有阳性反应。 在人类其他适应症的安全性试验中，一些仍在进行中。2-HOBA的有效性 已经建立了预防PH的小鼠，其机制表明它应该是有效的 为了逆转。在这里，我们通过测试2-HOBA逆转已建立的免疫缺陷的功效来准备2-HOBA的人体试验。 在两个单独或与二甲双胍联合的分子精确小鼠模型中， 人类和小鼠之间共有的疾病的血清生物标志物，用于早期反应指征， 用于指导人体试验。