Weibel - Palade Bodies - Sentinels of Acute Ischemia

Weibel - Palade Bodies - 急性缺血的哨兵

• 批准号: 8079698
• 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/8079698
• 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; Wound Healing; base; conditioning; cytokine; design; improved; injury and repair; insight; lysylproline; novel; preconditioning; 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)：主要研究者和其他实验室以前的研究已经令人信服地证明：a)内皮祖细胞(EPC)在对肾脏的缺血应激反应中动员；b)EPC在应激反应中存在内源性动员机制--其中之一是尿酸水平的激增；c)EPC参与肾脏保护；以及d)EPC参与缺血后器官的最终修复过程。这些发现表明，了解EPC动员的内在途径可以揭示一些新的组织保护和再生的分子机制，这些机制可以用于药物治疗。我们推测，EPC的动员和正确归巢不仅具有肾脏保护作用，而且是诱导药理性预适应的关键策略。1)针对嘌呤代谢途径的代谢产物，尤其是缺血后尿酸的可逆性激增和细胞因子，我们将定义从缺血器官释放的应激(或SOS)信号的化学特性，其中一些导致2)webel-Palade小体的胞吐和其成分的释放，如血管生成素-2、白细胞介素8和von Willebrand因子导致3)在系统动员EPC和植入受影响的器官促进其再生，同时创造促炎条件。我们将考察这两种趋势之间的平衡。通过Toll样受体直接或间接传递尿酸盐信号的可能性将在TLR-2和-4基因敲除小鼠身上进行研究。通过使用稳定的含有Lys-Pro的多肽来阻断缺血或尿酸反应中的Webel-Palade小体的胞吐，将评估这一途径在缺血后损伤中的作用；这种阻断也提供了一个独特的机会来选择这些细胞器的单个成分，这些成分以最小的促炎反应诱导最大的药理预适应。这两个步骤以前都没有在EPC动员的背景下进行过审查。这些问题的答案有望为组织修复定义一条新的内在途径(S)，包括通过缺血后尿酸激增和韦贝尔-帕拉德小体的胞吐作为内皮祖细胞动员的效应器的警报信号。完善这一途径对于实现确定药理前和后处理策略的长期目标将是至关重要的。公共卫生相关性：各种应激源造成的肾脏损伤仍然是医疗保健的主要问题。应激诱导内皮祖细胞动员(EPC)是新近发现的肾脏保护的内在机制之一。这项研究首次系统地研究了来自缺血肾脏的应激信号，以动员内皮祖细胞(主要是尿酸)，并探索控制这一过程的分子机制，长期目标是设计药物预适应和后处理的策略。此外，研究EPC在糖尿病小鼠急性肾损伤中的功能及其植入，可能为糖尿病或代谢综合征增加肾脏损伤易感性的潜在机制提供见解。