Peripheral Nicotinic Cholinergic and Inflammatory Dysfunction in Aging

衰老过程中的外周烟碱胆碱能和炎症功能障碍

基本信息

批准号：
8306201
负责人：
LORISE C GAHRING
金额：
$ 23.49万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2014-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): A recently recognized role of nicotinic acetylcholine receptors (nAChR) is to regulate inflammatory cytokine expression. As we age, changes in nAChR expression are observed and these correlate with dysregulation of inflammatory status. This raises the relatively unexplored possibility that these age-related changes are mechanistically related. The skin exhibits age-related changes in nAChR expression and proinflammatory cytokine expression, and it is an experimentally accessible model for defining how nAChR expression impacts on both primary and secondary inflammatory responses. Recent key findings in the mouse skin include: 1) the nAChRa7 subtype modulates expression of suppressor of cytokine signaling 3 (SOCS3); 2) the nAChR:inflammatory interaction involves p38MAPkinse responsive pathways; and 3) SOCS3 expression is dysregulated in both a7KO adult mice and aged mice whose a7 expression is dramatically decreased. Therefore, the goal of the research proposed is to elucidate mechanisms of interaction between the nAChR and the inflammatory cytokines in regulating peripheral responses as we age. Overall Project Hypothesis: Age-related shifts in nAChR expression by peripheral organs modulate local dysregulation of inflammatory responses through SOCS3 and p38MAPK-dependent pathways. SPECIFIC AIM 1. Goal: To measure age-related changes in the inflammatory status and response by the skin and correlate these to age-related changes in nAChR expression. Hypothesis: Tissue-specific changes in nAChR expression will correspond to age-related alterations in responses to an inflammatory challenge. SPECIFIC AIM 2. Goal: To define the intracellular signaling mechanism(s) that control interactions between nAChRs and inflammatory cytokines, and determine if alterations within these pathways correspond to age related dysfunction in nAChR:inflammatory balance. Hypothesis: nAChRa7 impacts upon inflammatory status through modulating intracellular signaling cascades affecting SOCS3 expression. SPECIFIC AIM 3. Goal: One hypothesis of aging is that chronic inflammation speeds the progression of aging. Because a7KO mice demonstrate an exaggerated inflammatory response; chronic inflammatory stimulation should result in more rapid aging in terms of inflammatory cytokine production by the skin. Hypothesis: Adult mice lacking the expression of a7 will respond to chronic inflammatory challenge by exhibiting inflammatory characteristics consistent with more advanced aged phenotypes. PUBLIC HEALTH RELEVANCE: Neuronal nicotinic receptors (nAChR) are normally studied for their role in the brain where they regulate processes leading to addiction. In addition to neurons, cells throughout the body express nAChRs where they to help regulate normal inflammatory responses to invading organisms. As we age, nAChR expression in peripheral tissues and the brain decreases. In turn, the ability of our body to control normal inflammatory responses also decreases. This proposal will investigate how nAChR expression can contribute to regulating inflammation through different pathways, especially as we age. Further, we will determine if changes in nAChR expression shape the progression of normal aging of the skin through altering the important balance between normal and excessive inflammation.

描述（由申请人提供）：烟碱乙酰胆碱受体（NACHR）最近公认的作用是调节炎症细胞因子的表达。随着年龄的增长，观察到NACHR表达的变化，这些变化与炎症状态的失调相关。这增加了相对未开发的可能性，即这些与年龄相关的变化在机械上相关。皮肤表现出与年龄相关的NACHR表达和促炎细胞因子表达的变化，并且是一个实验可访问的模型，用于定义NACHR表达如何影响对原发性和继发性炎症反应的影响。小鼠皮肤中最近的主要发现包括：1）NACHRA7亚型调节细胞因子信号抑制剂的表达3（SOCS3）； 2）NACHR：炎症相互作用涉及p38mapkinse响应途径； 3）SOCS3表达在A7KO成年小鼠和老年小鼠中均大大降低。因此，提出的研究的目的是阐明NACHR与炎症细胞因子之间在调节外周反应时的相互作用机制。总体项目假设：外围器官通过SOCS3和p38MAPK依赖性途径调节炎症反应的局部失调，与年龄相关的NACHR表达转移。特定目的1。目标：测量皮肤与年龄相关的炎症状态和反应的变化，并将其与NACHR表达的年龄相关的变化相关联。假设：NACHR表达的组织特异性变化将对应于对炎症挑战的反应中与年龄相关的变化。特定目标2。目标：定义控制NACHR和炎症细胞因子之间相互作用的细胞内信号传导机制，并确定这些途径内的变化是否与NACHR中的年龄相关功能障碍相对应：炎症平衡。假设：NACHRA7通过调节影响SOCS3表达的细胞内信号传导级联反应对炎症状态的影响。特定目的3。目标：衰老的一个假设是慢性炎症会加快衰老的发展。因为A7KO小鼠表现出夸张的炎症反应；慢性炎症刺激应导致皮肤炎症细胞因子的产生更快。假设：缺乏A7表达的成年小鼠将通过表现出与更高级老年表型一致的炎症特征来应对慢性炎症挑战。公共卫生相关性：通常研究神经元烟碱受体（NACHR），因为它们在大脑中的作用在调节导致成瘾过程的过程中。除了神经元外，整个体内的细胞表达了NACHRS，以帮助调节对入侵生物的正常炎症反应。随着年龄的增长，NACHR在外周组织中的表达和大脑的表达降低。反过来，我们身体控制正常炎症反应的能力也会降低。该建议将调查NACHR表达如何通过不同的途径来调节炎症，尤其是随着年龄的增长。此外，我们将确定NACHR表达的变化是否会通过改变正常炎症和过度炎症之间的重要平衡来塑造皮肤正常老化的进展。