Regulatory Role of Growth Hormone Secretagogue Receptor

生长激素促分泌受体的调节作用

• 批准号: 7208829
• 负责人: ROY G SMITH
• 金额: $ 37.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208829
• 关键词: Address; Adenylate Cyclase; Age; Aging; Agonist; Anterior Pituitary Gland; Area; Attenuated; Behavioral; Biological; Biological Assay; Biology of Aging; Bone Density; Brain; Cells; Cellularity; Chronic; Clinical; Clinical Trials; Coupling; Cyclic AMP; Desire for food; Dopamine; Dopamine Receptor; Elderly; Fluorescence Resonance Energy Transfer; Frail Elderly; G-Protein-Coupled Receptors; Growth; Health; Heterodimerization; Hippocampus (Brain); Homodimerization; Hormone Receptor; Hormones; Human; Insulin-Like Growth Factor I; Investigation; Isoenzymes; Knockout Mice; Laboratories; Learning; Localized; Mediating; Mediator of activation protein; Memory; Midbrain structure; Modification; Molecular; Moods; Mus; Muscle; Names; Nervous System Physiology; Neuraxis; Neurons; Parkinson Disease; Pathway interactions; Pertussis Toxin; Phase; Phenotype; Physiological; Progress Reports; Protein Kinase C Inhibitor; Quality of life; Receptor Signaling; Regulation; Research Design; Research Personnel; Role; Series; Signal Transduction; Somatostatin; Somatostatin Receptor; Somatotropin; Structure; Testing; Therapeutic Intervention; Translating; age related; attenuation; base; bone; cell growth; clinical application; cognitive function; dopaminergic neuron; expression cloning; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; growth hormone-releasing hormone receptor; human GPRC5C protein; immune function; improved; in vivo; mimetics; prevent; programs; receptor; receptor coupling; restoration; small molecule; sound; young adult

DESCRIPTION (provided by applicant): Our objective is to provide therapeutic intervention that will maintain high quality of life during aging. We developed small molecules that restore the physiological profile of episodic growth hormone (GH) release in the elderly to that of young adults and then cloned the orphan G-protein coupled receptor (GPCR) mediator involved, naming it the growth hormone secretagogue receptor (GHS-R). Subsequently, Kojima identified the endogenous agonist, ghrelin; hence, the small molecule GHS-R agonists are referred to as ghrelin mimetics. In the frail elderly, chronic administration of a ghrelin mimetic, MK677, to rejuvenate the GH axis, was accompanied by increased bone density, lean mass and strength. Therefore, we concluded that MK677 rescued an age-dependent deficit in endogenous ghrelin signaling. Aside from the GH axis, this deficit could have more profound consequences during aging because the GHS-R (ghrelin receptor) localizes to neurons regulating mood, memory and learning. The dopamine receptor subtype-1 (D1R) is coexpressed in these same neurons, implicating ghrelin as a modulator of dopamine signaling. Indeed, in cells coexpressing GHS-R and D1R, ghrelin amplifies dopamine-induced accumulation of cAMP. To investigate the broad significance of neuromodulation by ghrelin, GHS-R modulation of D1R, GH-releasing hormone (GHRH) receptor, and somatostatin receptors (sst5 and sst2) signaling will be compared. These GPCR partners are endogenously coexpressed with the GHS-R in vivo and regulate cAMP signaling. Mechanistic studies will investigate: adenylyl cyclase (AC) activity; identifying AC-isozymes involved; modification of Ga subunits; ¿y-subunit scavenging; GHS-R/GPCR heterodimerization. Specific Aims: define the molecular mechanism of amplification of dopamine D1R-induced cAMP accumulation caused by co-activation of the ghrelin receptor (GHS-R), and test the hypothesis in wildtype, ghrelin-/- and ghrelin receptor knockout mice (Ghsr-/-) that ghrelin-mediated amplification occurs in vivo to enhance signaling in D1R and GHS-R expressing neurons resulting in behavioral changes; determine the molecular mechanism of how ghrelin activation of GHS-R amplifies GHRH receptor-mediated cAMP accumulation and contrasts with amplification of D1R-induced cAMP accumulation; determine the molecular mechanism of how ghrelin activation of GHS-R attenuates the inhibitory effects sst5-signaling on cAMP accumulation, compare with sst2, and determine whether sst5 and sst2 are coexpressed with the GHS-R in brain. Because of ghrelin's broad modulatory role on signaling in the brain, rescuing age-related deficits in endogenous ghrelin signaling has broad human health implications. Augmentation of dopamine signaling by ghrelin in the elderly is directly relevant to aging and Parkinson's disease, because learning and memory are improved by increasing cAMP accumulation in neurons. We hypothesize that clinical use of ghrelin mimetics will translate to improved cognitive function in the elderly.

描述(由申请人提供)：我们的目标是提供治疗干预，在衰老过程中保持高质量的生活。我们开发了小分子来恢复老年人阵发性生长激素(GH)释放的生理特征，然后克隆了涉及的孤儿G蛋白偶联受体(GPCR)介体，将其命名为生长激素促分泌素受体(GHS-R)。随后，小岛确定了内源性激动剂Ghrelin；因此，小分子GHS-R激动剂被称为Ghrelin模拟剂。在虚弱的老年人中，长期服用Ghrelin模拟物MK677来恢复GH轴的活力，伴随着骨密度、瘦质量和强度的增加。因此，我们得出结论，MK677挽救了内源性Ghrelin信号的年龄依赖性缺陷。除了生长激素轴，这种缺陷在衰老过程中可能会产生更深远的后果，因为GHS-R(Ghrelin受体)定位于调节情绪、记忆和学习的神经元。多巴胺受体亚型-1(D1R)在这些神经元中共同表达，暗示Ghrelin是多巴胺信号的调制器。事实上，在共表达GHS-R和D1R的细胞中，Ghrelin放大了多巴胺诱导的cAMP积累。为了探讨Ghrelin对神经调节的广泛意义，我们将比较GHS-R对D1R、生长激素释放激素(GHRH)受体和生长抑素受体(Sst5和Sst2)信号的调节作用。这些GPCR伙伴在体内与GHS-R内源性共表达，并调节cAMP信号。机制研究将调查：腺酰环化酶(AC)活性；鉴定涉及的AC同工酶；GA亚基的修饰；Y亚基清除；GHS-R/GPCR异二聚化。具体目的：明确Ghrelin受体(GHS-R)共激活导致多巴胺D1R诱导cAMP积聚的分子机制，并在野生型、Ghrelin-/-和Ghrelin受体敲除小鼠(GHSR-/-)中验证Ghrelin介导的扩增在体内发生的假说，以增强D1R和GHS-R表达神经元的信号，导致行为改变；确定Ghrelin激活Ghrelin如何放大GHRH受体介导的cAMP积聚的分子机制，并与扩增D1R诱导的cAMP积聚进行对比；确定GHS-R的Ghrelin激活如何减弱sst5信号对cAMP积累的抑制作用的分子机制，并与Sst2进行比较，并确定sst5和Sst2是否与GHS-R在脑内共表达。由于Ghrelin对大脑信号的广泛调节作用，挽救与年龄相关的内源性Ghrelin信号缺陷具有广泛的人类健康意义。在老年人中，Ghrelin增强多巴胺信号与衰老和帕金森病直接相关，因为学习和记忆是通过增加神经元中cAMP的积累来改善的。我们假设Ghrelin模拟物的临床应用将转化为改善老年人的认知功能。