Peripheral Nicotinic Cholinergic and Inflammatory Dysfunction in Aging

描述（由申请人提供）：最近认识到烟碱乙酰胆碱受体（nAChR）的作用是调节炎性细胞因子的表达。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有关。这就提出了一个相对未被探索的可能性，即这些与年龄有关的变化是机械相关的。皮肤表现出nAChR表达和促炎细胞因子表达的年龄相关变化，并且它是用于定义nAChR表达如何影响原发性和继发性炎症反应的实验可访问模型。最近在小鼠皮肤中的关键发现包括：1）nAChRa 7亚型调节细胞因子信号传导抑制因子3（SOCS 3）的表达; 2）nAChR：炎症相互作用涉及p38 MAPK激酶应答途径;和3）SOCS 3表达在α 7 KO成年小鼠和α 7表达显著降低的老年小鼠中均失调。因此，提出的研究的目标是阐明nAChR和炎症细胞因子之间的相互作用机制，在调节外周反应，因为我们的年龄。总体项目假设：外周器官nAChR表达的变化通过SOCS 3和p38 MAPK依赖性途径调节局部炎症反应失调具体目标1.目标：测量皮肤炎症状态和反应的年龄相关变化，并将其与nAChR表达的年龄相关变化相关联。假设：nAChR表达的组织特异性变化将对应于对炎症挑战的响应中的年龄相关改变。具体目标2.目标：确定控制nAChR和炎性细胞因子之间相互作用的细胞内信号传导机制，并确定这些通路内的变化是否对应于nAChR：炎症平衡中的年龄相关功能障碍。假设：nAChRa 7通过调节影响SOCS 3表达的细胞内信号级联影响炎症状态。具体目标3.目的：衰老的一个假说是慢性炎症加速衰老的进程。由于a7 KO小鼠表现出过度的炎症反应;慢性炎症刺激应导致皮肤产生炎症细胞因子方面的更快衰老。假设：缺乏a7表达的成年小鼠将通过表现出与更晚期的衰老表型一致的炎症特征来响应慢性炎症攻击。公共卫生相关性：神经元烟碱受体（nAChR）通常被研究它们在大脑中的作用，在那里它们调节导致成瘾的过程。除了神经元，全身的细胞都表达nAChR，它们帮助调节对入侵生物的正常炎症反应。随着年龄的增长，外周组织和大脑中的nAChR表达减少。反过来，我们的身体控制正常炎症反应的能力也会下降。该提案将研究nAChR表达如何通过不同的途径调节炎症，特别是随着年龄的增长。此外，我们将确定nAChR表达的变化是否通过改变正常和过度炎症之间的重要平衡来塑造皮肤正常老化的进展。

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.