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

描述（由申请人提供）：控制炎症反应对预防感染是有益的；然而，过度失调的炎症有助于关节炎、癌症、心血管疾病和许多自身免疫性疾病的发病机制。本课题主要研究低密度脂蛋白受体相关蛋白（sLRP-1）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在炎症期间从细胞表面脱落的机制。LRP-1是低密度脂蛋白受体基因家族的成员，该家族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。成熟的LRP-1包括515 kDa的a链和85 kDa的跨膜p链。在循环中检测到的LRP-1的Shed形式包含a链（515 kDa亚基）和3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竞争共同配体而产生的。在本研究计划中，我们将验证我们的主要假设，即sLRP-1在体内具有抗炎生物活性，可能代表一种新的内源性抗炎因子。在这个应用中，提出了三个具体目标。在目标1中，我们建议阐明LRP- 1脱落的机制，并确定负责这一过程的蛋白酶。Aim 2建立在初步数据的基础上，我们已经证明sLRP-1在lps诱导的炎症过程中在循环中积累。我们将继续这些研究，以便了解LPS如何调节野生型小鼠血浆中sLRP-1的积累。研究还将测试循环中的sLRP-1是否主要来自血细胞。在Aim 3中，我们将确定内源性产生和外源性给药的sLRP-1是否调节对LPS的炎症反应的发展。了解sLRP-1在炎症期间在血液中积累的生理意义和sLRP-1的抗炎潜能是关键目标。此外，我们将在体内循环中对sLRP-1进行药理学表征。研究将确定sLRP-1的血浆半衰期、分布半衰期和器官生物分布等参数，这些参数对任何药物的开发都是必不可少的。该项目将有助于我们了解炎症的病理生理，并提供关于sLRP-1如何代表一种新的内源性抗炎因子的关键信息。

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.