NEUROPEPTIDES AND CARCADIAN RHYTHMS DURING AGING

衰老过程中的神经肽和昼夜节律

• 批准号: 2429299
• 负责人: PHYLLIS M. WISE
• 金额: $ 18.23万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-17 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429299
• 关键词: aging; antisense nucleic acid; arginine vasopressin; astrocytes; cell cell interaction; circadian rhythms; complementary DNA; enzyme linked immunosorbent assay; gene expression; gene induction /repression; hormone receptor; immunocytochemistry; in situ hybridization; laboratory rat; messenger RNA; mixed tissue /cell culture; neurons; neuropharmacology; neurotransmitter transport; oligonucleotides; receptor expression; serotonin; somatostatin; suprachiasmatic nucleus; vasoactive intestinal peptide

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.

描述：（申请人的摘要）许多生理过程和 几乎所有真核生物中的行为都表现出内源性昼夜节律 节奏性。 在哺乳动物中，上核上核（SCN） 下丘脑驱动这些节奏并充当关键神经 起搏器。 在衰老期间，许多节奏表现出较短的时期 进步，幅度减弱和时间对异步和 分散。 在老年人中，这导致 内分泌节奏的睡眠活动节奏和可能的不同步 导致健康状况不佳。 该提议的长期目标是 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 SCN的协调，同步和精确的节奏特征 （2）这些机制的变化如何影响起搏器功能下降 在衰老期间。 血管活性肠肽（VIP）和生长抑素（SRIF） 作为差分传入输入的沟通者，可能会扮演关键角色， 昼夜节律的传出信息或调节器的传出者 夹带。 因此，申请人将使用细胞和分子 解决以下特定目的的方法：（1）表征 VIP和SRIF的时间模式（A）分泌和细胞肽 表达和（b）器官型中mRNA和原发性转录水平 包含SCN的培养物。 （2）评估5HT相移的能力 VIP和SRIF分泌在器官型切片中的节奏，并比较此 它具有分散细胞培养物相位转移的能力。 （3）模仿 通过靶向抑制VIP和/或SRIF对VIP和SRIF的影响 通过反义寡核苷酸施用的反义寡核苷酸或 分散细胞培养物并确定对模式的影响 其他肽的表达。 申请人将评估5HT是否可以 当VIP或SRIF为 被压制。 申请人指出，即将到来的信息将加深我们的 了解基础的细胞和分子机制 SCN的节奏活动以及这些机制的变化如何导致 昼夜节律功能的老化状非同步。 与IRPG一起 由Drs提交。邓肯和麦克马洪，他们将使用 任何单一的方法和方法都无法 研究者。