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: 8232766
• 负责人: DONALD R SENGER
• 金额: $ 50.83万
• 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/8232766
• 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. PUBLIC HEALTH RELEVANCE: Ischemic disease, caused by insufficient blood flow, is a serious clinical problem associated with aging, diabetes, hypercholesterolemia, and obesity. Ischemic disease results from progressive functional decline of blood vessels and the consequences are debilitating and often fatal. The objectives of the proposed research are to identify new effective strategies, using natural products, for successfully treating this disease.

描述（由申请人提供）：组织缺血，定义为提供氧气和营养的血流量不足，是与衰老、糖尿病、高胆固醇血症和肥胖相关的严重临床问题。缺血是由大血管和小血管的进行性功能衰退引起的，其后果是使人虚弱，往往是致命的。提出的研究计划的具体目标是确定有效的，机械特征的策略，采用天然产物，克服目前的障碍，以减轻缺血。具体目的是：（Aim 1a）在小鼠模型中研究口服狼疮芽孢杆菌（AE-BL）水提物对缺血驱动的功能失调血管生成的治疗作用，并确定对组织氧合和存活的益处；（Aim 1b）确定细胞和分子机制；（Aim 2a）确定构成未分离AE-BL全部活性的单个成分，其稳定内皮细胞（EC）细胞骨架和EC-EC连接；（Aim 2b）鉴定纯化组分的组合，以治疗功能失调，缺血驱动的血管生成，类似于未分离的提取物。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，血流）以及由此导致的组织氧合和组织存活的改善将在缺血驱动血管生成的小鼠模型中进行定义。EC信号通路和细胞骨架调节机制，通过AE-BL治疗功能失调的血管形态发生，从而改善血管生成，将与体外EC一起定义。这些体外试验也将用于鉴定具有重要生物活性的AE-BL纯化组分，以及鉴定具有类似于未分离AE-BL生物活性的纯化组分的组合。因此，提出的研究计划旨在阐明一种新的策略，用于治疗功能失调的血管生成和减轻组织缺血的未分离AE-BL，并确定体现这一重要生物活性的特定化合物。