Shed LDL Receptor Related Protein 1 (sLRP-1) and Inflammation

脱落 LDL 受体相关蛋白 1 (sLRP-1) 与炎症

• 批准号: 7808211
• 负责人: Matvey Gorovoy
• 金额: $ 2.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-07-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7808211
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthritis; Attenuated; Autoimmune Process; Biodistribution; Biological; Biological Markers; Blood; Blood Cells; Blood Circulation; Cardiovascular Diseases; Cell Culture Techniques; Cell surface; Cells; Coupled; Data; Development; Disease; Disintegrins; Edema; Endocytosis; Endotoxins; Exhibits; Functional disorder; Gene Family; Goals; Half-Life; Homeostasis; Human; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Interferon Type II; LDL-Receptor Related Protein 1; Laboratories; Ligands; Lipopolysaccharides; Lipoproteins; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Metalloproteases; Molecular; Mus; Organ; Pathogenesis; Pathway interactions; Peptide Hydrolases; Peripheral nerve injury; Pharmacologic Substance; Physiological; Plasma; Process; Production; Receptor Gene; Regulation; Reporting; Research Project Grants; Research Proposals; Rodent Model; Role; Signal Transduction; Source; Stimulus; Testing; Time; Tissues; Wild Type Mouse; base; cytokine; extracellular; in vivo; macrophage; member; mouse model; neutrophil; novel; promoter; protein function; receptor; receptor mediated endocytosis; response

DESCRIPTION (provided by applicant): A controlled inflammatory response is beneficial when providing protection against infection; however dysregulated excessive inflammation contributes to disease pathogenesis in arthritis, cancer, cardiovascular disease, and a host of autoimmune conditions. This research project focuses on the role of the shed form of low density lipoprotein receptor related protein (sLRP-1) in inflammation. Our long-term goal is to understand the anti-inflammatory role of sLRP-1 in vivo and describe the mechanisms by which sLRP-1 is shed from the cell surface during inflammation. LRP-1 is a member of the LDL receptor gene family, which includes type I trans-membrane proteins that function in receptor-mediated endocytosis and cell signaling. Mature form of LRP-1 includes the 515 kDa a-chain and 85 kDa transmembrane p-chain. Shed form of LRP-1, which is detected in circulation, contains the a-chain (515 kDa subunit) and a 55 kDa fragment of the 3-chain. Recent evidence from our lab showed that in a rodent model of peripheral nerve injury, sLRP-1 expressed anti-inflammatory activity that did not result from competition with membrane-anchored LRP-1 for common ligands. In this research proposal we will test our major hypothesis that sLRP-1 exhibits anti- inflammatory biological activity in vivo and may represent a novel endogenous anti-inflammatory factor. In this application three specific aims are proposed. In Aim 1, we propose to elucidate the mechanism of LRP- 1 shedding and identify the protease responsible for this process. Aim 2 builds on preliminary data in which we have demonstrated that sLRP-1 accumulates in circulation during LPS-induced inflammation. We will continue these studies so we can understand how LPS challenge regulates accumulation of sLRP-1 in plasma in wild-type mice. Studies will also be conducted to test whether sLRP-1 in circulation is primarily blood cells originated. In Aim 3, we will determine whether endogenously-produced and exogenously- administered sLRP-1 regulates development of inflammation in response to LPS. Understanding the physiological significance of sLRP-1 accumulation in blood during inflammation and sLRP-1 anti- inflammatory potential are the critical objectives. Additionally, we will perform pharmacologic characterization of sLRP-1 in circulation in vivo. Studies will be made to determine parameters such as plasma half-life, distribution half-life, and organ biodistribution of sLRP-1 that are essential for the development of any pharmaceutical. This project will contribute to our understanding of the pathophysiology of inflammation and provide critical information regarding how sLRP-1 may represent a novel endogenous anti-inflammatory factor.

描述（由申请人提供）：当提供针对感染的保护时，受控的炎症反应是有益的;然而，失调的过度炎症有助于关节炎、癌症、心血管疾病和许多自身免疫性病症中的疾病发病机制。本研究项目的重点是低密度脂蛋白受体相关蛋白（sLRP-1）的脱落形式在炎症中的作用。我们的长期目标是了解sLRP-1在体内的抗炎作用，并描述sLRP-1在炎症过程中从细胞表面脱落的机制。LRP-1是LDL受体基因家族的成员，其包括在受体介导的内吞作用和细胞信号传导中起作用的I型跨膜蛋白。LRP-1的成熟形式包括515 kDa的α链和85 kDa的跨膜β链。在循环中检测到的LRP-1的脱落形式含有α链（515 kDa亚基）和β链的55 kDa片段。我们实验室最近的证据表明，在周围神经损伤的啮齿动物模型中，sLRP-1表达的抗炎活性不是由于与膜锚定的LRP-1竞争常见配体而产生的。在这项研究中，我们将测试我们的主要假设，即sLRP-1在体内表现出抗炎生物活性，并可能代表一种新的内源性抗炎因子。在本申请中，提出了三个具体目标。在目标1中，我们提出阐明LRP- 1脱落的机制，并确定负责这一过程的蛋白酶。目的2建立在我们已经证明sLRP-1在LPS诱导的炎症过程中在循环中积累的初步数据的基础上。我们将继续这些研究，以便我们能够了解LPS攻击如何调节野生型小鼠血浆中sLRP-1的积累。还将进行研究以测试循环中的sLRP-1是否主要来源于血细胞。在目的3中，我们将确定内源性产生和外源性施用的sLRP-1是否响应于LPS调节炎症的发展。了解sLRP-1在炎症过程中在血液中积累的生理意义和sLRP-1抗炎潜力是关键目标。此外，我们将在体内循环中进行sLRP-1的药理学表征。将进行研究以确定对于任何药物开发必不可少的参数，例如sLRP-1的血浆半衰期、分布半衰期和器官生物分布。该项目将有助于我们了解炎症的病理生理学，并提供有关sLRP-1如何可能代表一种新的内源性抗炎因子的关键信息。