ASTROCYTE ACTIVATION BY SMALL MOLECULE P2Y1 AGONISTS FOR TREATMENT OF TBI

小分子 P2Y1 激动剂激活星形胶质细胞治疗 TBI

• 批准号: 8979659
• 负责人: JAMES D LECHLEITER
• 金额: $ 42.02万
• 依托单位: ASTROCYTE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979659
• 关键词: Accident and Emergency department; Achievement; Acute; Adverse effects; Affect; Agonist; American; Animal Model; Animals; Antioxidants; Area; Astrocytes; Attention; Biological Markers; Biomedical Engineering; Brain; Brain Concussion; Brain Edema; Brain Injuries; Businesses; Capital; Caring; Cause of Death; Cell Death; Cell Survival; Child; Clinical; Cognitive; Data; Development; Dose; Drug Kinetics; Edema; Emotional; Evaluation; Excision; Experimental Designs; Family suidae; Frequencies; Glial Fibrillary Acidic Protein; Gliosis; Glutamates; Goals; Grant; Growth Factor; Healed; Homeostasis; Hospitals; Hour; Human; Hyperactive behavior; In Vitro; Industry; Injury; Investments; Ions; Lead; Leadership; Link; Medical; Mitochondria; Modeling; Molecular; Motor; Mus; Neonatal; Neuroglia; Neurologic; Neurons; Oxidative Stress; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase III Clinical Trials; Principal Investigator; Process; Production; Purinoceptor; Receptor Signaling; Regimen; Research; Safety; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Sports; Supporting Cell; Testing; Texas; Therapeutic; Therapeutic Human Experimentation; Time; Toddler; Toxic effect; Traumatic Brain Injury; Treatment Protocols; Universities; Work; animal efficacy; brain tissue; cell type; cellular targeting; cost; disability; drug candidate; drug development; drug metabolism; emergency service responder; excitotoxicity; experience; extracellular; healing; improved; in vivo; intravenous injection; mild traumatic brain injury; mouse model; neuronal survival; neuroprotection; novel strategies; operation; prevent; professor; public health relevance; relating to nervous system; research and development; restoration; small molecule; social anxiety; success; young adult

 DESCRIPTION (provided by applicant): Traumatic brain injuries (TBI) are an area of significant unmet need with no approved therapeutics and a national burden of ~$77 billion annually. Astrocyte Pharmaceuticals is developing a small molecule pharmaceutical agent that would be administered by intravenous injection by emergency responders or a medical professional within 24 hours of injury to limit neuronal damage and cell death. The proprietary approach at Astrocyte Pharmaceuticals differs significantly from historical neuroprotective attempts in that it focuses on a non-neuronal cell type, the astrocyte, which has only recently received broader attention as an important cellular target for successful therapeutic research. Molecular activation of astrocytes enhances multiple healing mechanisms including protection against edema, glutamate excitotoxicity and oxidative stress. Preliminary data demonstrate significant neuroprotective benefits of these molecules in mouse models when administered within 30 minutes, 3 hours and even at 24 hours post-injury. The goal of this STTR Phase I project is to establish the ability of these small molecules to significantly enhance the inherent neuroprotective activity of astrocytes in both small and large animal TBI models. The project aims to optimize the treatment protocol (dosing, timing and frequency) that maximizes the in vitro neuronal viability benefits of ~6 candidate molecules, utilize an in vivo mouse TBI model to select a lead candidate that maximizes reduction in the magnitude and duration of whole brain edema and reactive gliosis biomarkers, and validate that the efficacy of the lead candidate in a study with a toddler piglet TBI model.

 描述（由申请人提供）：创伤性脑损伤（TBI）是一个显著未满足需求的领域，没有批准的治疗方法，每年的国家负担约为770亿美元。Astrocyte Pharmaceuticals正在开发一种小分子药剂，可以在受伤后24小时内由紧急救援人员或医疗专业人员静脉注射，以限制神经元损伤和细胞死亡。Astrocyte Pharmaceuticals的专有方法与历史上的神经保护尝试有很大不同，因为它专注于非神经元细胞类型，星形胶质细胞，它最近才受到更广泛的关注，成为成功治疗研究的重要细胞靶点。星形胶质细胞的分子活化增强了多种愈合机制，包括对水肿、谷氨酸兴奋性毒性和氧化应激的保护。初步数据表明，当在损伤后30分钟、3小时甚至24小时内给药时，这些分子在小鼠模型中具有显著的神经保护益处。该STTR I期项目的目标是建立这些小分子在小型和大型动物TBI模型中显着增强星形胶质细胞固有神经保护活性的能力。该项目旨在优化治疗方案（给药、时间和频率），使约6种候选分子的体外神经元活力益处最大化，利用体内小鼠TBI模型选择一种主要候选物，使全脑水肿和反应性神经胶质增生生物标志物的幅度和持续时间最大化减少，并验证主要候选物在幼儿仔猪TBI模型研究中的疗效。