NEUROPEPTIDES AND CARCADIAN RHYTHMS DURING AGING

描述：(申请人摘要)许多生理过程和 几乎所有真核生物的行为都表现出内源性的昼夜节律 节奏性。哺乳动物的视交叉上核(SCN) 下丘脑驱动这些节律，并充当关键神经 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，衰减幅度和时间去同步和 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同步化 导致健康状况不佳。这项建议的长期目标是 了解(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、同步和精确的节奏是SCN和 (2)这些机制的改变如何影响起搏器功能的下降 在衰老过程中。血管活性肠肽和生长抑素 可以扮演作为不同传入输入的通信者的关键角色， 昼夜节律传出信息的广播者或 夹带。因此，申请者将使用细胞和分子 解决以下具体目标的方法：(1)确定 VIP和SRIF(A)分泌与细胞多肽的时序关系 表达，以及(B)在器官型中的mRNA和初级转录本的水平 含有SCN的培养物。(2)评价5-羟色胺的移相能力 器官切片中VIP和SRIF的分泌节律及其比较 在分散的细胞培养中进行相变的能力。(3)模仿 靶向抑制VIP和/或SRIF对VIP和SRIF的影响 通过将反义寡核苷酸注射到器官切片或 分散的细胞培养，并确定对模式的影响 另一种多肽的表达。申请者将评估5HT是否可以 VIP或SRIF时，这些多肽的节律发生静止相移 被压制了。 申请者表示，即将到来的信息将加深我们的 对细胞和分子机制的理解 SCN的节律性活动以及这些机制的变化如何导致 类似衰老的昼夜节律功能的去同步化。与IRPG一起 由邓肯博士和麦克马洪博士提交，他们将使用一个 广泛的方法和途径，这是任何单一的 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.