Remedying dysfunctional angiogenesis and tissue ischemia with Barleria lupulina

用羽扇豆芽孢杆菌治疗功能失调的血管生成和组织缺血

• 批准号: 8432035
• 负责人: DONALD R SENGER
• 金额: $ 47.51万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8432035
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Aging; Amputation; Architecture; Biological; Biological Factors; Blindness; Blood Vessels; Blood flow; Calpain; Clinical; Cytoskeleton; Defect; Diabetes Mellitus; Disease; Endothelial Cells; Esters; Gene Targeting; Glycogen Synthase Kinases; Hypoxia; Impaired wound healing; In Vitro; Individual; Intercellular Junctions; Ischemia; Limb structure; Medicinal Plants; Metabolic; Molecular; Morphogenesis; Myocardial Infarction; Necrosis; Nutrient; Obesity; Oral Administration; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Philippines; Research; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Snakes; Source; Stroke; Tissue Survival; Tissues; Tube; Ulcer; Vascular Endothelial Growth Factors; Viola; angiogenesis; aqueous; calpain inhibitor; cytokine; design; functional decline; functional improvement; hypercholesterolemia; improved; in vitro Assay; in vivo; meetings; mouse model; new growth; research study; response; tissue oxygenation; transcription factor

DESCRIPTION (provided by applicant): Tissue ischemia, defined as insufficient blood flow for providing oxygen and nutrients, is a serious clinical problem associated with aging, diabetes, hypercholesterolemia, and obesity. Ischemia results from progressive functional decline of large and small blood vessels and the consequences are debilitating and often fatal. The specific objectives of the proposed research plan are to identify effective, mechanistically characterized strategies, employing natural products, for overcoming current barriers to alleviation of ischemia. The specific aims are: (Aim 1a) Investigate oral administration of aqueous extracts of Barleria lupulina (AE-BL) for remedying ischemia-driven dysfunctional angiogenesis in mouse models, and define benefits for tissue oxygenation and survival; (Aim 1b) Define cellular and molecular mechanisms; (Aim 2a) Identify the individual components constituting the full activity of un-fractionated AE-BL, which stabilize the endothelial cell (EC) cytoskeleton and EC-EC junctions; (Aim 2b) Indentify combinations of purified components that remedy dysfunctional, ischemia-driven angiogenesis similarly to the un-fractionated extract. The specific vascular improvements (e.g., vessel architecture, lumen formation, network integration, barrier integrity, blood flow) provided by oral administration of AE-BL, and the resulting improvement in tissue oxygenation and tissue survival will be defined in mouse models of ischemia-driven angiogenesis. EC signaling pathways and cytoskeleton-regulating mechanisms through which AE-BL remedies dysfunctional vascular morphogenesis and thereby improves angiogenesis will be defined with ECs in vitro. These in vitro assays also will be employed to identify purified components of AE-BL with important bioactivity and to identify combinations of purified components comprising bioactivity similar to un-fractionated AE-BL. Thus, the proposed research plan is designed to illustrate a new strategy for remedying dysfunctional angiogenesis and alleviating tissue ischemia with un-fractionated AE-BL and also to identify specific compounds that embody this important biological activity.

描述(申请人提供)：组织缺血，定义为供氧和营养不足的血液流动，是与衰老、糖尿病、高胆固醇血症和肥胖症相关的严重临床问题。缺血是大小血管功能进行性下降的结果，其后果是虚弱的，往往是致命的。拟议研究计划的具体目标是确定有效的、机械特征的策略，利用天然产品，克服目前缓解缺血的障碍。其具体目的是：(目的1a)研究口服羽扇豆水提物(AE-BL)在小鼠模型上纠正缺血引起的功能性血管生成的益处，并确定对组织氧合和存活的益处；(目的1b)确定细胞和分子机制；(目的2a)确定构成未经分离的AE-BL全部活性的单独成分，它稳定内皮细胞(EC)细胞骨架和EC-EC连接；(目的2b)鉴定与未经分离的提取物相似地修复功能障碍的缺血驱动的血管生成的纯化成分的组合。口服AE-BL提供的特定血管改善(例如，血管结构、管腔形成、网络整合、屏障完整性、血液流动)，以及由此产生的组织氧合和组织存活率的改善，将在缺血驱动的血管生成的小鼠模型中确定。EC信号通路和细胞骨架调节机制，通过AE-BL改善血管形态发生障碍，从而促进血管生成，将在体外与内皮细胞进行定义。这些体外试验也将被用于鉴定具有重要生物活性的AE-BL的纯化成分，并鉴定含有类似于未分离的AE-BL的生物活性的纯化成分的组合。因此，提出的研究计划旨在阐明一种新的策略，用不分离的AE-BL来纠正功能障碍的血管生成和减轻组织缺血，并鉴定体现这一重要生物活性的特定化合物。