A Bifunctional Katp Channel Activator and Redox Mimetic for BPD

BPD 的双功能 Katp 通道激活剂和氧化还原模拟物

基本信息

批准号：
8449796
负责人：
Kanneganti Murthy
金额：
$ 26.69万
依托单位：
RADIKAL THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449796
关键词：
3-nitrotyrosine Acute Acute Lung Injury Adverse effects Albumins Alveolar Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Aspirate substance Attenuated Autopsy Biological Biological Models Blood Vessels Breathing Bronchopulmonary Dysplasia CCL2 gene CSF3 gene Clinical Clinical Data Collagen Colorado Complex Cytoplasmic Protein Development Disease Dose Drug Controls Drug Targeting Eotaxin Evaluation Failure Fibrosis Functional disorder Gene Expression Genes Gestational Age Glutathione Glutathione Disulfide Granulocyte-Macrophage Colony-Stimulating Factor Growth Heart Histologic Human Hyperglycemia Hyperoxia Hypotension Hypoxia IL4 gene Impairment In Vitro Infarction Infiltration Inflammation Inflammatory Injury Interferons Interleukin-10 Interleukin-12 Interleukin-13 Interleukin-15 Interleukin-17 Interleukin-2 Interleukin-3 Interleukin-5 Interleukin-6 Interleukin-7 Interleukin-9 Ischemic Preconditioning LIF gene Laboratories Lipid Peroxidation Lung Lung diseases Macrophage Colony-Stimulating Factor Macrophage Inflammatory Protein-1 Malondialdehyde Mechanics Mediating Mitochondria Modeling Mus Myocardial Ischemia NADPH Oxidase NF-kappa B Neonatal Newborn Respiratory Distress Syndrome Nitric Oxide Synthase Nuclear Translocation Oxidants Oxidation-Reduction Pathogenesis Pathologic Peripheral Peroxonitrite Phase Physiological Pinacidil Placebo Control Placebos Play Pneumonia Poly Adenosine Diphosphate Ribose Potassium Channel Premature Birth Premature Infant Production Property Protein Isoforms Proteins Pulmonary Fibrosis Pulmonary Gas Exchange Pyrrolidines RANTES Randomized Rattus Recombinants Relative (related person)Reperfusion Injury Resuscitation Right Ventricular Hypertrophy Rodent Role Route Safety Signal Transduction Small Business Innovation Research Grant Small Inducible Cytokine A3 Smooth Muscle Stress Structure Structure of parenchyma of lung Superoxide Dismutase Superoxides TNF gene Tail Testing Therapeutic Tissues Trichrome stain United States National Institutes of Health Universities Vascular Endothelial Growth Factors Vascular remodeling Ventricular Ventricular Fibrillation Xanthine Oxidase arteriole base catalase catalyst clinically relevant density human CXCL5 protein in vivo intraperitoneal lung injury mimetics muscle hypertrophy neutrophil novel premature premature lungs prevent prospective protein expression public health relevance pulmonary arterial hypertension pup pyrrolidine small molecule superoxide dismutase 1 thioredoxin reductase

项目摘要

DESCRIPTION (provided by applicant): Radikal Therapeutics is developing a novel small molecule therapy (R-801) for neonatal prematurity that triggers an endogenous cytoprotective defense and thereby blocks pulmonary inflammation and acute lung injury (ALI). R-801 is formed from the covalent fusion of 2 moieties with demonstrated tissue protective properties: 1) a mito-K+-ATP channel activating domain derived from pinacidil, and 2) a pyrrolidine nitroxide domain (hydroxymethylproxyl, "HMP") that acts as a broad-spectrum redox decomposition catalyst. R-801 is more potent than classic K+-ATP channel openers (e.g. pinacidil) and is free of the classic side-effects of sarcolemmal K+-ATP channel activation (hyperglycemia, ventricular fibrillation, hypotension). Our overarching hypothesis is that R-801 will prophylactically block th progression of neonatal respiratory distress syndrome to bronchopulmonary dysplasia (BPD). In a murine model of hypohalous redox lung injury induced by Cl2 inhalation, R-801 resuscitation reduced histologic injury, diminished neutrophil (PMN) infiltration, blocked nuclear translocation of NF-kB, and diminished the degradation of the anti-inflammatory cytoplasmic protein IkB¿ (p<0.01). R-801 does not activate the sarcolemmal K+-ATP channel, as shown by its failure in rats to induce hypotension, hyperglycemia, or ventricular fibrillation. We now seek to establish that R-801 attenuates changes of pulmonary vascular and alveolar structure in a hyperoxic model of BPD in neonatal rats. In conjunction with the Abman laboratory (University of Colorado), RTX will carry out a prospective dose-escalation study wherein lung injury is induced by subjecting 2-day old rat pups to hyperoxia for 10 days. A sham control (no hyperoxia, no R-801) will be compared to a drug control (R-801, no hyperoxia), R-801 (3, 10, 30 mg/kg qd), and vehicle control (D5W) administered by an intraperitoneal (IP) route for 3 weeks, a period characterized in this model system by progressive lung fibrosis, pulmonary arterial hypertension (PAH), and hypoalveolarization. Lung tissue taken at necropsy will be analyzed for pulmonary vascular structure and growth, alveolarization, lipid peroxidation (malondialdehyde), glutathione (GSH/GSSG ratio), peroxynitrite formation (3-nitrotyrosine), poly(ADP-ribose) formation, fibrosis (Mason Trichrome staining for collagen), R- 801 levels, and the protein expression of pro-inflammatory genes, including eotaxin, G-CSF, GM-CSF, IFN-?, IL-1¿, IL-2, IL4, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17, IP-10, KC, LIF, LIX, MCP-1, M-CSF, MIG, MIP-1¿, MIP-1¿, MIP-2, RANTES, TNF-¿, and VEGF. The heart will also be analyzed for evidence of PAH (as evidenced by right ventricular hypertrophy). Progression to the Phase 2 NIH SBIR will require that treatment with R-801 dose-dependently demonstrates (at p<0.05 2-tailed) relative to the vehicle control: > 30% increase in alveolar density, and > 30% reductions in pulmonary fibrosis, pulmonary arteriolar smooth muscle hypertrophy, right ventricular mass, PMN infiltration, lipid peroxidation, peroxynitrite and poly(ADP-ribose) formation, pro-inflammatory gene expression, and oxidized glutathione.

描述（由申请人提供）：Radikal Therapeutics 正在开发一种针对早产儿的新型小分子疗法 (R-801)，该疗法可触发内源性细胞保护防御，从而阻止 R-801 形成的肺部炎症和肺部急性损伤 (ALI)。具有组织保护特性的 2 个部分的共价融合：1) 源自吡那地尔的 mito-K+-ATP 通道激活结构域，以及2) 吡咯烷氮氧结构域（羟甲基丙氧基，“HMP”）作为广谱氧化还原分解催化剂，比经典的 K+-ATP 通道开放剂（例如吡那地尔）更有效，并且没有典型的副作用。肌膜 K+-ATP 通道激活（高血糖、心室颤动、低血压）的影响。 R-801 将预防性阻止新生儿呼吸窘迫综合征发展为支气管肺发育不良 (BPD)。在 Cl2 吸入引起的下卤氧化还原性肺损伤的小鼠模型中，R-801 复苏可减少组织学损伤，减少中性粒细胞 (PMN) 浸润。，阻断 NF-kB 的核转位，并减少抗炎细胞质蛋白 IkB 的降解(p<0.01)。R-801 不会激活肌膜 K+-ATP 通道，如它在大鼠中未能引起低血压、高血糖或心室颤动所示。我们现在试图确定 R-801 可以减弱肺血管的变化。 RTX 将与 Abman 实验室（科罗拉多大学）合作开展一项关于新生大鼠 BPD 高氧模型中的肺泡结构和肺泡结构的研究。一项前瞻性剂量递增研究，将 2 天大的幼鼠置于高氧环境下 10 天诱导肺损伤，将假手术对照（无高氧，无 R-801）与药物对照（R-801，无高氧）进行比较。 )、R-801 (3、10、30 mg/kg qd) 和载体对照 (D5W) 通过腹膜内 (IP) 途径施用 3 周，该模型系统中以进行性肺纤维化、肺动脉高压（PAH）和肺泡化程度低为特征的时期将分析尸检时采集的肺组织的肺血管结构和生长、肺泡化、脂质过氧化（丙二醛）、谷胱甘肽（GSH/GSSG）。）比率），过氧亚硝酸盐形成（3-硝基酪氨酸），聚（ADP-核糖）形成，纤维化（梅森胶原三色染色）、R-801 水平以及促炎基因的蛋白质表达，包括嗜酸细胞活化趋化因子、G-CSF、GM-CSF、IFN-α、IL-1¿ , IL-2, IL4, IL-3, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL -15、IL-17、IP-10、KC、LIF、LIX、MCP-1、M-CSF、MIG、MIP-1¿ ，MIP-1?? 、MIP-2、RANTES、TNF-¿还将分析心脏的 PAH 证据（如右心室肥大所证明），进展到 NIH SBIR 2 期将需要 R-801 剂量依赖性治疗（p<0.05 2 尾）。 ) 相对于载体对照：肺泡密度增加 > 30%，肺纤维化、肺小动脉平滑肌肥大减少 > 30%，右心室质量、中性粒细胞浸润、脂质过氧化、过氧亚硝酸盐和聚（ADP-核糖）形成、促炎基因表达和氧化型谷胱甘肽。