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

• 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
• 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

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（由适用提供）：Radikal Therapeatics正在开发一种新型的小分子治疗（R-801），用于新生儿早产，从而触发内源性细胞保护防御，从而阻止肺部感染和急性肺损伤（ALI）。 R-801由2个部分具有组织保护特性的部分的共价融合形成：1）源自Pinacidil的Mito-K+-ATP通道激活结构域，以及2）吡咯烷硝基氧化物结构域（羟基甲基甲基甲状腺素，HMP”，“ HMP”），该替代了catspects Proccts Procceptips Procceptions proppproict propppromproum condosty condoxty。 R-801比经典的K+-ATP通道开瓶器（例如Pinacidil）更有潜力，并且不含肌膜K+-ATP通道激活的经典副作用（高血糖，心室纤维化，高血压）。我们的总体假设是，R-801将预防性阻止新生儿呼吸窘迫综合征对支气管肺发育不良（BPD）的进展。在CL2吸入诱导的低气压氧化还原肺损伤的鼠模型中，R-801复苏减少了组织学损伤，中性粒细胞减少（PMN）浸润，阻塞NF-KB的核易位，并减少了抗炎性细胞性细胞质蛋白质蛋白质蛋白质IKB <0.0.01 <0.01 <0011） R-801不会激活肌膜K+-ATP通道，如大鼠在大鼠中诱导低血压，高血糖或心室纤颤所示所示。现在，我们试图确定R-801减弱了新生大鼠BPD高氧模型中肺血管和肺泡结构的变化。与Abman实验室（科罗拉多大学）一起，RTX将进行一项前瞻性剂量降低研究，其中通过将2天老的大鼠幼崽患有高氧诱导肺损伤10天。假对照（无高氧，无R-801）将与药物控制（R-801，无高氧），R-801（3、10、30 mg/kg QD）和载体控制（D5W）进行比较低盐肺化。 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- - 和VEGF。心脏还将被分析以获取PAH的证据（如右心肥大所证明）。发展为2阶段NIH SBIR将需要使用R-801剂量依赖性的治疗相对于车辆对照表明（p <0.05 2尾）：肺泡密度> 30％，肺纤维化降低> 30％，肺纤维化降低> 30％聚（ADP-核糖）形成，促炎基因表达和氧化谷胱甘肽。