Peripheral Nicotinic Cholinergic and Inflammatory Dysfunction in Aging

描述（由申请人提供）：最近认识到尼古丁乙酰胆碱受体（nAChR）的作用是调节炎症细胞因子的表达。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失调有关。这提出了一种相对未被探索的可能性，即这些与年龄相关的变化与机制有关。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，这是一个实验可获得的模型，用于定义nAChR表达如何影响原发性和继发性炎症反应。最近在小鼠皮肤中的主要发现包括：1)nAChRa7亚型调节细胞因子信号传导抑制因子3 （SOCS3）的表达；2) nAChR：炎症相互作用涉及p38map激酶反应途径；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。因此，本研究的目的是阐明nAChR和炎症细胞因子在调节外周反应中的相互作用机制。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依赖途径调节局部炎症反应失调。具体目标1。目的：测量皮肤炎症状态和反应的年龄相关变化，并将这些变化与nAChR表达的年龄相关变化联系起来。假设：nAChR表达的组织特异性变化将与炎症反应的年龄相关变化相对应。具体目标2。目的：确定控制nAChR与炎症细胞因子相互作用的细胞内信号传导机制，并确定这些通路中的改变是否与nAChR炎症平衡的年龄相关功能障碍相对应。假设：nAChRa7通过调节影响SOCS3表达的细胞内信号级联来影响炎症状态。具体目标3。目的：关于衰老的一个假设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；慢性炎症刺激会导致皮肤产生炎症细胞因子，从而加速衰老。假设：缺乏a7表达的成年小鼠将通过表现出与更先进的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：神经尼古丁受体（nAChR）在大脑中调节导致成瘾的过程中的作用通常被研究。除了神经元，全身的细胞都表达nachr，它们在那里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。本研究将探讨nAChR表达如何通过不同途径，特别是随着年龄的增长，调节炎症。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.