NEUROPEPTIDES AND CARCADIAN RHYTHMS DURING AGING

描述：（申请人摘要）许多生理过程和 事实上，所有真核生物的行为都表现出内源性昼夜节律， 节奏性 在哺乳动物中，视交叉上核（SCN） 下丘脑驱动这些节奏，并作为关键的神经 起搏器 在衰老过程中，许多节律表现出较短的周期，相位 进展，衰减幅度和时间去极化， 碎片化 在老年人中，这会导致 睡眠-活动节律和内分泌节律的去极化， 导致健康状况不佳。 这项建议的长期目标是 理解（1）翻译的关键细胞和分子机制 单个神经化学物质和细胞的振荡进入 协调，同步和精确的节奏特征的SCN和 (2)这些机制的变化如何影响起搏器功能的下降 在老化过程中。 血管活性肠肽（VIP）和生长抑素（SRIF） 可能作为差异传入输入的沟通者发挥关键作用， 昼夜节律时间传出信息的广播者或 夹带 因此，申请人将使用细胞和分子 方法，以解决以下具体目标：（1）表征 VIP和SRIF（a）分泌和细胞肽时间模式 表达，和（B）器官型中mRNA和初级转录物的水平 含有SCN的培养物。 (2)评估5 HT的相移能力 VIP和SRIF分泌的节律，并比较这一点 它在分散的细胞培养物中的相移能力。 (3)模仿 通过靶向抑制VIP和/或SRIF，年龄对VIP和SRIF的影响 通过给予器官型切片的反义寡核苷酸， 分散的细胞培养，并确定对模式的影响， 另一种肽的表达。 申请人将评估5 HT是否可以 当VIP或SRIF被激活时， 抑制 申请人表示，即将提供的信息将加深我们的 理解细胞和分子机制， SCN的节律性活动以及这些机制的变化如何导致 生理机能的衰老样去极化。 与IRPG一起 由邓肯和麦克马洪博士提交，他们将集中在这一领域使用一个 广泛的方法和途径，这是不可能与任何单一的 调查员

DESCRIPTION: (Applicant's abstract) Many physiological processes and behaviors in virtually all eukaryotes exhibit endogenous circadian rhythmicity. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus drives these rhythms and serves as the critical neural pacemaker. During aging, many rhythms exhibit shorter periods, phase advances, attenuated amplitudes and temporal desynchronization and fragmentation. In elderly humans, this results in fragmentation of sleep-activity rhythms and desynchronization of endocrine rhythms which may lead to poor health. The long-term objectives of this proposal are to understand (1) the critical cellular and molecular mechanisms that translate the oscillations of individual neurochemicals and cells into the coordinated, synchronized and precise rhythms characteristic of the SCN and (2) how changes in these mechanisms influence declining pacemaker function during aging. Vasoactive intestinal peptide (VIP) and somatostatin (SRIF) may play key roles as communicators of differential afferent input, broadcasters of efferent messages of circadian time or modulators of entrainment. Therefore, the applicant will use cellular and molecular methods to address the following specific aims: (1) characterize the temporal pattern of VIP and SRIF (a) secretion and cellular peptide expression, and (b) levels of mRNA and primary transcript in organotypic cultures containing the SCN. (2) assess the ability of 5HT to phase shift the rhythms of VIP and SRIF secretion in organotypic slices and compare this to its ability to phase shift in dispersed cell cultures. (3) mimic the effects of age on VIP and SRIF by targeted suppression of VIP and/or SRIF via antisense oligonucleotides administered to organotypic slices or dispersed cell cultures and determine the effect on the pattern of expression of the other peptide. The applicant will assess whether 5HT can still phase shift the rhythms of these peptides when VIP or SRIF is suppressed. The applicant states that forthcoming information will deepen our understanding of the cellular and molecular mechanisms that underlie rhythmic activity of the SCN and how changes in these mechanisms may lead to aging-like desynchronization of circadian function. Together with the IRPGs submitted by Drs. Duncan and McMahon, they will focus on this area using a broad array of methods and approaches that is not possible with any single investigator.