Weibel - Palade Bodies - Sentinels of Acute Ischemia

Weibel - Palade Bodies - 急性缺血的哨兵

• 批准号: 8298636
• 负责人: MICHAEL S GOLIGORSKY
• 金额: $ 33.89万
• 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/8298636
• 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; Health; 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; base; conditioning; cytokine; design; improved; injury and repair; insight; lysylproline; novel; preconditioning; purine; purine metabolism; regenerative; repaired; response; stem; stressor; tissue repair; 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）：主要研究者和其他实验室的既往研究已令人信服地证明：a）内皮祖细胞（EPC）响应于肾脏缺血性应激的动员; B）响应于应激的EPC动员的内源性机制的存在-其中之一由尿酸水平的激增控制; c）EPC参与缺血预处理的肾保护;和d）EPC参与缺血后器官的最终修复过程。这些发现表明，对EPC动员内在途径的了解可以揭示一些新的组织保护和再生的分子机制，这些机制可以在药学上利用。我们推测EPC的动员和适当归巢不仅具有肾保护作用，而且也是诱导药物预处理的关键策略。具体而言，将进行研究以建立导致EPC动员以响应压力的途径：1）关注嘌呤代谢途径的代谢物，特别是尿酸的可逆缺血后激增，以及细胞因子，我们将定义从缺血器官释放的应激（或SOS）信号的化学身份，其中一些导致2）威-帕二氏体的胞吐作用和它们的成分如血管生成素-2、白细胞介素-8和血管性血友病因子的释放，导致3）EPC的全身动员和受影响器官的移植改善其再生，与此同时也会引发炎症将审查这两种趋势之间的平衡。将使用TLR-2和TLR-4敲除小鼠研究通过Toll样受体直接或间接尿酸盐信号传导的可能性。通过使用稳定的含Lys-Pro的肽（其阻断响应于缺血或尿酸的韦伯-帕拉德体的胞吐作用），将评价该途径在缺血后损伤中的作用;该阻断还提供了选择这些细胞器的单个组分的独特机会，这些细胞器诱导最大的药理学预处理，具有最小的促炎反应。这两个步骤以前都没有在EPC动员的背景下进行过审查。预计这些问题的答案将定义一种新的内在途径，用于组织修复，包括通过缺血后尿酸激增和作为EPC动员效应物的韦伯-帕拉德体胞吐作用的警报信号传导。这一途径的完善将是至关重要的，在实现长期目标，确定药理学预处理和后处理的策略。公共卫生相关性：各种压力源引起的肾脏损伤仍然是医疗保健的一个主要问题。应激诱导的内皮祖细胞动员是近年来发现的肾脏保护的内在机制之一.这项研究首次系统地调查了缺血性肾脏产生的应激信号，以动员EPC（重点是尿酸），并探索管理这一过程的分子机制，长期目标是设计药理学预处理和后处理策略。此外，对EPC的功能能力及其在急性肾损伤的糖尿病小鼠中的植入的研究可以提供对糖尿病或代谢综合征中肾损伤易感性增加的潜在机制的见解。