2-HOBA for Treatment of Pulmonary Hypertension

2-HOBA 治疗肺动脉高压

基本信息

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
项目类别：
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

项目摘要

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.

项目概要尽管肺动脉高压 (PH) 代谢问题的普遍存在早已为人所知十年来，有关这一问题本质的大量新细节为干预提供了机会。一个细胞和动物实验工作以及人类早期试验的结合表明，这些代谢问题是 PH 的部分原因，线粒体赖氨酸失活脱乙酰酶SIRT3是调节代谢缺陷的中心节点。存在一个恶性循环，其中触发事件或突变会增加活性氧 (ROS)，从而产生活性脂质，从而加合物并使 SIRT3 失活，引起代谢变化，导致 ROS 进一步增加。在这里，我们打破该循环使用 2-HOBA，这是一种小分子，可以有效吸收体内反应性脂质，并具有积极的作用。导致对人类其他适应症的安全性试验，其中一些仍在进行中。 2-HOBA 的功效已经建立了预防小鼠 PH 的方法，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 逆转已建立的单独或与二甲双胍联合使用两种分子精确的小鼠模型中的疾病，并通过检查人类和小鼠之间共享的疾病血清生物标志物，用于早期反应迹象，可以用于指导人体试验。