Weibel - Palade Bodies - Sentinels of Acute Ischemia

Weibel - Palade Bodies - 急性缺血的哨兵

• 批准号: 7921552
• 负责人: MICHAEL S GOLIGORSKY
• 金额: $ 37.78万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-25 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921552
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Address; Adenosine; Adhesions; Affect; Angiopoietin-2; Bone Marrow; Chemicals; Competence; Complex; Diabetes Mellitus; Diabetic mouse; Endothelial Cells; Endothelium; Engraftment; Equilibrium; Exocytosis; Goals; Healthcare; Heart; Homing; IL8 gene; Immunoelectron Microscopy; Individual; Inflammation; Inflammatory; Injury; Inosine; Interleukin-8; Ischemia; Ischemic Preconditioning; Kidney; Knockout Mice; Knowledge; Laboratories; Laboratory Study; Lead; Metabolic Pathway; Metabolic syndrome; Molecular; Natural regeneration; Nature; Organ; Organelles; Outcome; Pathway interactions; Peptides; Predisposition; Principal Investigator; Process; Progenitor Cell Engraftment; Purines; Reaction; Research Personnel; Role; Sentinel; Signal Transduction; Site; Son of Sevenless Proteins; Spleen; Stem cells; Stress; Surveys; Testing; Time; Tissues; Toll-like receptors; Urate; Uric Acid; Vascular Cell Adhesion Molecule-1; Weibel-Palade Bodies; Wound Healing; base; conditioning; cytokine; design; improved; injury and repair; insight; lysylproline; novel; preconditioning; public health relevance; purine; purine metabolism; regenerative; repaired; response; stem; stressor; trend; von Willebrand Factor

DESCRIPTION (provided by applicant): Previous studies from the Principal Investigator's and other laboratories have convincingly demonstrated a) the mobilization of endothelial progenitor cells (EPC) in response to ischemic stress to the kidney; b) the existence of endogenous mechanisms for EPC mobilization in response to stress - one of those is governed by a surge in uric acid level; c) EPC's participation in renoprotection of ischemic preconditioning; and d) EPC's participation in the eventual repair processes of a post-ischemic organ. These findings infer that the knowledge of intrinsic pathways for EPC mobilization could reveal some novel molecular mechanisms of tissue protection and regeneration, which could be utilized pharmaceutically. We hypothesize that mobilization and proper homing of EPC is not only renoprotective, but also represents a key strategy for induction of pharmacological preconditioning. Specifically, studies will be conducted to establish the pathways leading to EPC mobilization in response to stress: 1) focusing on the metabolites of purine metabolic pathway, especially a reversible post-ischemic surge in uric acid, and cytokines, we shall define the chemical identities of stress (or SOS) signals discharged from the ischemic organ, some of which lead to 2) exocytosis of Weibel-Palade bodies and release of their constituents, such as angiopoietin-2, interleukin- 8 and von Willebrand factor resulting 3) in the systemic mobilization of EPC and engraftment of the affected organ improving its regeneration and, at the same time creating pro-inflammatory conditions. The balance between these two trends will be examined. The possibility of direct or indirect urate signaling via Toll-like receptors will be studied using TLR-2 and -4 knockout mice. Through the use of a stable Lys-Pro-containing peptide which blocks exocytosis of Weibel-Palade bodies in response to ischemia or uric acid, the role of this pathway in post-ischemic injury will be evaluated; this blockade also provides a unique opportunity to select individual components of these organelles which induce maximal pharmacologic preconditioning with minimal pro-inflammatory reaction. Neither of these steps has been previously examined in the context of EPC mobilization. It is anticipated that answers to these questions will define a novel intrinsic pathway(s) for tissue repair involving alarm signaling via post-ischemic surge in uric acid and exocytosis of Weibel-Palade bodies as an effector in EPC mobilization. Refinement of this pathway will be crucial in accomplishing the long-term goal of defining the strategies for pharmacological pre- and post-conditioning. PUBLIC HEALTH RELEVANCE: Kidney injury in response to variety of stressors remains a major problem for health care. Stress- induced mobilization of endothelial progenitor cells (EPC) represents one of the recently discovered intrinsic mechanisms for renoprotection. The study proposed offers the first systematic survey of stress signals emanating from the ischemic kidney to mobilize EPC (focusing on uric acid) and to explore molecular mechanisms governing this process with the long-term goal of designing strategies for pharmacological preconditioning and postconditioning. Furthermore, studies on the functional competence of EPC and their engraftment in diabetic mice subjected to acute kidney injury may provide insights into potential mechanisms of increased predisposition to renal injury in diabetes or metabolic syndrome.

描述（由申请人提供）：先前的研究人员和其他实验室的研究令人信服地证明了a）动员内皮祖细胞（EPC），以应对肾脏的缺血性压力； b）存在于应激的响应EPC动员的内源性机制 - 其中之一受尿酸水平的激增。 c）EPC参与缺血性预处理的重生保护； D）EPC参与了缺血后器官的最终修复过程。这些发现推断，对EPC动员的内在途径的了解可以揭示一些新型的组织保护和再生分子机制，这些机制可以在药物上使用。我们假设动员和适当的EPC归巢不仅是重新保护的，而且代表了诱导药理预处理的关键策略。 Specifically, studies will be conducted to establish the pathways leading to EPC mobilization in response to stress: 1) focusing on the metabolites of purine metabolic pathway, especially a reversible post-ischemic surge in uric acid, and cytokines, we shall define the chemical identities of stress (or SOS) signals discharged from the ischemic organ, some of which lead to 2) exocytosis of Weibel-Palade bodies and release of their组成部分，例如血管生成素-2，白介素8和von willebrand因子，产生3），导致EPC的系统性动员和受影响器官的植入，以改善其再生并同时创造促炎条件。将检查这两个趋势之间的平衡。使用TLR-2和-4基因敲除小鼠，将研究通过Toll样受体进行直接或间接尿道信号传导的可能性。通过使用稳定的含Lys-Pro的肽，该肽可以响应缺血或尿酸来阻断毒素 - 甲虫的体外，该途径将评估这种途径在缺血后损伤中的作用；这种封锁还提供了一个独特的机会，可以选择这些细胞器的各个组件，这些组成部分会以最小的促炎反应诱导最大的药理预处理。这些步骤均未在EPC动员的背景下进行过研究。可以预料，这些问题的答案将定义一种新型的固有途径，用于组织修复，涉及尿酸的缺血后激增和蠕虫 - 甲状腺胞胎的警报信号传导，并作为EPC动员的效应子。该途径的完善对于实现定义药理学前和调查策略的长期目标至关重要。公共卫生相关性：应对多种压力源的肾脏损伤仍然是医疗保健的主要问题。压力诱导的内皮祖细胞（EPC）的动员是最近发现的肾脏固有机制之一。这项研究提出，对从缺血性肾脏发出的应力信号进行了首次系统调查，以动员EPC（专注于尿酸），并探索有关此过程的分子机制，其长期目标是设计用于药理预处理和术后调节的策略。此外，对EPC及其在急性肾脏损伤的糖尿病小鼠中植入的功能能力的研究可能会洞悉潜在的糖尿病或代谢综合征肾损伤易感性的机制。