Peripheral Nicotinic Cholinergic and Inflammatory Dysfunction in Aging

描述(申请人提供)：最近确认的烟碱型乙酰胆碱受体(NAChR)的作用是调节炎性细胞因子的表达。随着年龄的增长，可以观察到nAChR表达的变化，这些变化与炎症状态的调节失调有关。这提出了一种相对未知的可能性，即这些与年龄相关的变化是机械相关的。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，它是一个实验可用来确定nAChR表达如何影响原发和继发性炎症反应的模型。最近在小鼠皮肤上的主要发现包括：1)nAChRa7亚型调节细胞因子信号抑制因子3(SOCS3)的表达；2)nAChR：炎症相互作用涉及p38MAPkinse反应通路；以及3)在A7KO成年小鼠和A7表达显著降低的老年小鼠中，SOCS3表达均异常调节。因此，这项研究的目的是阐明nAChR和炎症细胞因子之间的相互作用机制，以调节我们年龄的外周反应。总体项目假设：外周器官nAChR表达的年龄相关变化通过SOCS3和p38MAPK依赖的途径调节局部炎症反应的失调。具体目的1.目的：测量皮肤炎症状态和反应的年龄相关变化，并将这些与年龄相关的nAChR表达变化联系起来。假设：nAChR表达的组织特异性变化将对应于炎症挑战反应中与年龄相关的变化。目的：明确控制nAChR和炎性细胞因子相互作用的细胞内信号机制(S)，并确定这些通路中的变化是否对应于nAChR：炎症平衡的增龄性功能障碍。假设：nAChRa7通过调节细胞内影响SOCS3表达的信号级联来影响炎症状态。具体目的3.目标：衰老的一个假说是慢性炎症加速了衰老的进程。因为A7KO小鼠表现出夸大的炎症反应；慢性炎症刺激应该会导致皮肤产生炎症细胞因子，从而导致更快的衰老。假设：缺乏A7表达的成年小鼠将通过表现出与更高级的老年表型一致的炎症特征来应对慢性炎症挑战。与公共健康相关：神经元尼古丁受体(NAChR)通常被研究为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nAChRs，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nAChR的表达减少。反过来，我们身体控制正常炎症反应的能力也会下降。这项提议将研究nAChR的表达如何通过不同的途径调节炎症，特别是在我们变老的时候。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影响皮肤正常衰老的进程。

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.