Increased sodium dependent glucose transport in the ischemic brain

缺血脑中钠依赖性葡萄糖转运增加

• 批准号: 8323456
• 负责人: Thomas J Abbruscato
• 金额: $ 30.05万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323456
• 关键词: Acidosis; Acute; Admission activity; Age; Behavioral; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brain Ischemia; Capillary Endothelial Cell; Carrier Proteins; Cause of Death; Cell model; Cerebral Ischemia; Cerebrum; Cessation of life; Characteristics; Clinical; Complex; Coupled; Data; Deterioration; Development; Diabetes Mellitus; Diabetic mouse; Disease; Drug Delivery Systems; Edema; Endothelial Cells; Foundations; Free Radicals; Functional disorder; Generations; Glucose; Glucose Transporter; Glycolysis; Health; Heart Diseases; Hyperglycemia; In Situ; In Vitro; Infarction; Injury; Insulin; Insulin Resistance; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Kinetics; Lead; Mediating; Membrane; Microdialysis; Middle Cerebral Artery Occlusion; Modeling; Morbidity - disease rate; Mus; Necrosis; Nerve Degeneration; Neurons; Outcome; Patients; Perfusion; Phlorhizin; Physiological; Physiology; Play; Positioning Attribute; Process; Proteins; Publishing; Recovery; Regulation; Reperfusion Injury; Reperfusion Therapy; Resistance; Risk; Role; SLC2A1 gene; Severities; Sodium; Streptozocin; Stroke; Swelling; Techniques; Testing; Time; Translational Research; Water; Work; acute stroke; blood glucose regulation; diabetic; diabetic patient; disability; expectation; glucose transport; immunoreactivity; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; mRNA Expression; mortality; non-diabetic; novel; patient population; pre-clinical; protein function; research study

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and disability in USA. Given that at least one third of stroke patients are hyperglycemic on admission, with most being diabetic, and 65 percent of diabetic patients die from some form of heart disease or stroke, the diabetic stroke patient provides opportunity for unique pharmacologic interventions to improve stroke outcome. Increased glucose supply post ischemic attack has also been associated with cellular acidosis and free radical generation which can exacerbate edema. Recent published and preliminary data from our lab suggest that blood-to-brain glucose transport in both the ischemic and diabetic brain is partially carried by the sodium dependent glucose cotransporter (SGLT1) in addition to the traditional glucose carrier (GLUT1). Blood-brain barrier activation of SGLT1 protein can have deleterious effects in brain ischemia since SGLT1 is known to transport 2Na+ and 210 water molecules for each glucose molecule transported, thus having the propensity to contribute to both vasogenic and cellular brain edema, a leading cause of stroke death. Our data suggests that SGLT1 inhibition, with phlorizin administration post ischemia, resulted in reduced SGLT1 substrate transport across the ischemic brain and improved neurodegeneration, free radical damage, and infarction and edema ratios. Thus we hypothesize that SGLT1 induction during ischemia/reperfusion (IR) and diabetes mellitus (DM) plays a central role in ischemic damage and edema formation. We will test this hypothesis in three specific aims using both in vitro and in vivo models of IR injury and a model of DM. AIM 1: Elucidate the functional "transport" role of BBB SGLT1 using in vitro and in vivo models of brain ischemia and DM. Working Hypothesis: Brain endothelial cells subjected to high glucose (HG) and/or IR will increase SGLT1 mediated transport. AIM 2: Determine the regulatory mechanisms for SGLT1 activity at the BBB during conditions of both IR and HG. Working Hypothesis: Conditions of HG and IR will regulate SGLT1 activity by availability of Na and PKC control of SGLT1 membrane insertion. AIM 3: Evaluate the effects of SGLT1 inhibition on brain ECF [glucose], edema and infarction ratios, behavioral endpoints, and penumbral injury after in vivo focal ischemia with and without DM. Working Hypothesis: SGLT1 inhibition will decrease brain ECF [glucose] and improve stroke outcome in streptozotocin (STZ) treated mice and age matched controls. An understanding of altered blood-brain barrier SGLT1 function, regulation and neuroprotective effects of inhibition during stroke and DM is vital to provide a foundation for the development of phlorizin and other SGLT1 specific inhibitors as potential neuroprotective strategies to treat brain ischemia in both diabetic and non-diabetic stroke patients.

描述（由申请人提供）：中风是美国的第三大死亡和残疾原因。鉴于至少有三分之一的中风患者在入院时是高血糖，大多数是糖尿病患者，而65％的糖尿病患者死于某种形式的心脏病或中风，糖尿病性中风患者为独特的药理干预提供了机会，以改善中风结果。缺血性发作后葡萄糖供应增加也与细胞酸中毒和自由基产生有关，这可能加剧水肿。来自我们实验室的最新发表和初步数据表明，除传统的葡萄糖载体（GLUT1）外，缺血性和糖尿病大脑中的血液到脑葡萄糖转运均由钠依赖性葡萄糖共转运蛋白（SGLT1）部分携带。 SGLT1蛋白的血脑屏障激活可能在脑缺血中具有有害作用，因为已知SGLT1可用于运输的每个葡萄糖分子的2NA+和210个水分子，因此具有加血管和细胞脑经科的倾向，这是Stroke死亡的主要原因。我们的数据表明，缺血后的SGLT1抑制作用导致SGLT1底物跨缺血性脑的运输减少，并改善了神经退行性，自由基损伤，梗死和浮肿比。因此，我们假设缺血/再灌注期间的SGLT1诱导（IR）和糖尿病（DM）在缺血性损伤和水肿形成中起着核心作用。我们将使用IR损伤的体外和体内模型和DM模型在三个特定目标中检验这一假设。 AIM 1：使用体外和体内脑缺血和DM的体内模型阐明BBB SGLT1的功能“转运”作用。工作假设：经受高葡萄糖（HG）和/或IR的脑内皮细胞将增加SGLT1介导的转运。 AIM 2：确定IR和HG条件下BBB的SGLT1活性的调节机制。工作假设：HG和IR的条件将通过对SGLT1膜插入的Na和PKC控制来调节SGLT1活性。 AIM 3：评估SGLT1抑制对脑ECF [葡萄糖]，水肿和梗塞比，行为终点和半肿瘤损伤的影响，患有和没有DM。工作假设：SGLT1抑制作用将减少脑ECF [葡萄糖]，并改善经过治疗的小鼠（STZ）治疗的小鼠和年龄匹配的对照组中的中风结果。对抑制作用和DM期间抑制的调节和神经保护作用的改变的理解对于为发展腓洛依蛋白和其他SGLT1特异性抑制剂的发展提供基础至关重要。