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Validation of Adenylosuccinate as a Novel Endogenous Pro-Angiogenic Factor in the Brain

腺苷琥珀酸作为大脑中新型内源性促血管生成因子的验证

基本信息

批准号：
10405070
负责人：
Mikhail Y Golovko
金额：
$ 46.82万
依托单位：
UNIVERSITY OF NORTH DAKOTA
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：
2021-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10405070
关键词：
Ablation Address Adult Aging Angiogenic Factor Animals Attenuated Behavioral Biochemical Biological Assay Blood Vessels Brain Brain Hypoxia-Ischemia Brain Injuries Brain Ischemia Calcium Cell Proliferation Cerebrum Chronic Clinical Core-Binding Factor Data Disease Drug Targeting Endothelial Cells FGF2 gene Financial compensation Genetic Models Glioblastoma Glycolysis Inhibition Hypoxia In Vitro Injections Intranasal Administration Intraventricular Injections Laboratories Link Mediating Metabolic Metabolic Brain Diseases Metabolic Diseases Modeling Molecular Mus Nerve Degeneration Neurons Neurosciences Nutrition Disorders Outcome Oxygen Pathologic Pathology Phenotype Phospholipase C Phospholipases A Production Public Health Pump Recovery Regulation Research Role Signal Transduction Stroke Techniques Testing Therapeutic Time Traumatic Brain Injury Validation Vascular Endothelial Growth Factors Vascular Endothelium Work adeno-associated viral vector angiogenesis attenuation base behavioral outcome brain endothelial cell cell type design in vivo in vivo imaging innovation knock-down minimally invasive mouse model neuronal survival neurotoxicity new therapeutic target normoxia novel overexpression receptor response therapeutic target tumor tumorigenesis two photon microscopy

项目摘要

Adult brain angiogenesis is required for adaptation to low energy conditions e.g. hypoxia and ischemia, and for recovery after brain injury. Decreased brain angiogenesis may cause brain ischemia, neurodegeneration, and damage during aging while increased angiogenesis is linked to tumorigenesis including glioblastoma among other pathologies. Thus, an understanding of the mechanisms regulating adult cerebral angiogenesis has both basic neuroscience and clinical/translational importance to therapeutic vessel modulation for these diseases. The present basic neuroscience project is designed to investigate a previously unrecognized mechanism for brain angiogenesis regulation through a novel endogenous pro-angiogenic factor, adenylosuccinate (AdSucc). Our preliminary studies have revealed that AdSucc has an important cellular signaling role in the brain rather than functioning just as a metabolic intermediate metabolite. We demonstrated, for the first time, that AdSucc activates angiogenesis in assays both in vitro and in vivo, and that AdSucc induces phospholipase C dependent increase in cytoplasmic calcium, suggesting a receptor dependent action. Both of these effects were activated under AdSucc endogenous concentrations found under low energy conditions in the brain, which are conditions that require angiogenesis for long term compensation. Based on our preliminary data, our central hypothesis is that AdSucc is a brain endogenous pro-angiogenic factor. Our long term objective is to better understand metabolic regulation for brain angiogenesis, and determine if AdSucc is a valid therapeutic target for treating conditions where aberrant angiogenesis is involved. To test our hypothesis, we have established and characterized a novel AdSucc synthase (ADSS) conditional knockdown (KO) mouse model that allows for spatial and temporal control of AdSucc attenuation. We have also established in our laboratory a minimally invasive assay to quantify brain angiogenesis in a living animal in vivo using two photon microscopy. Our central hypothesis will be tested via the following Specific Aims: 1. Determine the role of AdSucc in brain angiogenesis under chronic hypoxia. We will use brain vascular imaging in vivo to determine angiogenesis in wild type and ADSS conditional KO mice under normoxia and chronic hypoxia, and confirm data with histochemical and functional assays. 2. Determine the role of AdSucc in brain angiogenesis under normoxia. In this aim, we will determine if AdSucc induces brain angiogenesis independently of oxygen availability. Successful completion of these aims will test a novel mechanism for regulation of brain angiogenesis.

成人脑血管生成是适应低能量条件（例如缺氧和缺血）和适应低能量条件（例如缺氧和缺血）所必需的。脑损伤后的恢复脑血管生成减少可导致脑缺血、神经变性和脑损伤。衰老过程中的损伤，而增加的血管生成与肿瘤发生有关，包括胶质母细胞瘤，其他病理。因此，了解成人脑血管生成的调节机制，基础神经科学和对这些疾病的治疗性血管调节的临床/转化重要性。目前的基础神经科学项目旨在研究一种以前未被认识的机制，通过一种新的内源性促血管生成因子腺苷琥珀酸（AdSucc）调节脑血管生成。我们的初步研究表明，AdSucc在大脑中具有重要的细胞信号传导作用，而不仅仅是作为一种代谢中间产物。我们首次证明了AdSucc 在体外和体内试验中，AdSucc激活血管生成，并且AdSucc诱导磷脂酶C 细胞质钙依赖性增加，表明受体依赖性作用。这两种效应在脑中低能量条件下发现的AdSucc内源性浓度下被激活，这是需要血管生成来进行长期补偿的病症。根据我们的初步数据，中心假设是AdSucc是脑内源性促血管生成因子。我们的长远目标是更好地了解脑血管生成的代谢调节，并确定AdSucc是否是一种有效的治疗方法，用于治疗涉及异常血管生成的病症的靶点。为了验证我们的假设，建立并表征了一种新的AdSucc合酶（ADSS）条件性敲低（KO）小鼠模型其允许AdSucc衰减的空间和时间控制。我们还在实验室中建立了一个使用双光子显微镜在活体动物中进行微创测定以量化脑血管生成。我们的中心假设将通过以下具体目标进行检验：1.确定AdSucc在大脑中的作用慢性缺氧下的血管生成。我们将在体内使用脑血管成像来确定血管生成，野生型和ADSS条件性KO小鼠在常氧和慢性缺氧下，并确认数据与组织化学和功能测定。2.确定AdSucc在常氧条件下脑血管生成中的作用。在这个目标中，我们将确定是否AdSucc诱导脑血管生成独立的氧可用性。这些目标的成功完成将测试一种新的机制来调节脑血管生成。