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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：创伤性脑损伤（TBI）是一个没有批准的治疗，每年未经批准的疗法的巨大需求的领域，每年烧伤约770亿美元。星形胶质细胞药物正在开发一种小分子药物，该药物将在受伤后的24小时内由紧急响应者或医疗专业人员管理，以限制神经元损伤和细胞死亡。星形胶质细胞药物的专有方法与历史神经保护尝试差异很大，因为它的重点是非神经元细胞类型，即星形胶质细胞，该类型最近才引起广播公司的关注，作为成功治疗研究的重要细胞靶标。星形胶质细胞的分子激活增强了多种愈合机制，包括防止水肿，谷氨酸兴奋性毒性和氧化应激。初步数据表明，当30分钟，3小时甚至在受伤后24小时内给药时，在小鼠模型中这些分子的显着神经保护益处。该STTR I期项目的目的是确定这些小分子在小动物TBI模型中显着增强星形胶质细胞的遗传神经保护活性的能力。该项目旨在优化治疗方案（剂量，时机和频率），以最大化〜6个候选分子的体外神经元的生存力益处，利用体内小鼠TBI TBI模型选择一个铅候选模型，以最大程度地减少整个大脑和反应性生物标志的较小的幅度和效率，从而最大程度地降低了较小TBI模型。