Regulatory Role of Growth Hormone Secretagogue Receptor

生长激素促分泌受体的调节作用

• 批准号: 7794836
• 负责人: ROY G SMITH
• 金额: $ 38.74万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7794836
• 关键词: Adenylate Cyclase; Age; Aging; Agonist; Area; Behavioral; Binding; Bone Density; Brain; CREB1 gene; Cell Line; Cells; Cellularity; Cessation of life; Chemosensitization; Clinical; Complex; Coupling; Cyclic AMP; Dopamine; Dopamine Receptor; Elderly; Fluorescence; Frail Elderly; Funding; GTP-Binding Proteins; Growth; Health; Hippocampus (Brain); Hormones; Human; In Situ Hybridization; In Vitro; Individual; Insulin-Like Growth Factor I; Investigation; Knock-in Mouse; Knockout Mice; Laboratories; Learning; MK-677; Measures; Mediating; Memory; Metabolism; Midbrain structure; Molecular; Moods; Movement; Mus; Muscle; Names; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurons; Oxidative Stress; Pathway interactions; Phenotype; Production; Progress Reports; Property; Receptor Signaling; Reporting; Research; Research Personnel; Role; Series; Signal Transduction; Signal Transduction Pathway; Somatotropin; Substantia nigra structure; Testing; The Sun; Therapeutic Intervention; Tyrosine 3-Monooxygenase; UCP2 protein; Ventral Tegmental Area; age related; attenuation; base; bone mass; clinical application; cognitive function; design; dopaminergic neuron; expression cloning; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; homologous recombination; human GPRC5C protein; immune function; immunocytochemistry; impression; improved; in vivo; mimetics; mutant; oxidative damage; prevent; programs; receptor; receptor coupling; research study; restoration; small molecule; stoichiometry; tau Proteins; young adult

DESCRIPTION (provided by applicant): Our objective is to provide therapeutic intervention that will extend health span during aging. The discovery of the ghrelin mimetic MK-0677 was a milestone discovery in aging research. MK-0677 rejuvenated the growth hormone (GH) axis in the frail elderly which was accompanied by increased bone density, lean mass and strength. It appears that MK-0677 rescued an age-dependent deficit in endogenous ghrelin signaling; evidence continues to emerge in support of this conclusion. Besides restoring neurons regulating the GH axis, the GHS-R (ghrelin receptor) localizes to neurons regulating mood and cognitive function. The dopamine receptor subtype-1 (D1R) is coexpressed in these neurons, implicating ghrelin as a modulator of dopamine signaling. In vitro studies support this notion and show that ghrelin amplifies dopamine-induced accumulation of cAMP by formation of GHS-R/D1R heterodimers. Because learning and memory are improved by augmentation of cAMP accumulation in neurons, rescuing impaired endogenous ghrelin signaling by selectively increasing cAMP in D1R neurons with ghrelin mimetics has potential benefit for the elderly. The hypothesis that ghrelin augmentation of D1R signaling and formation of GHS-R/D1R heterodimers occurs in vivo and manifests behavioral effects will be tested using ghrelin-/- and Ghsr-/- mice. Ghrelin has neuroprotective properties and is a positive regulator of uncoupling protein-2 (UCP2) expression. UCP2 protects dopamine neurons from oxidative damage and death induced by 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP). Therefore, the hypothesis that ghrelin prevents loss of D1R neurons by increasing UCP2 expression will also be tested. Crosstalk between GHS-R and D1R causing amplification of cAMP production in selective neurons that coexpress GHS-R and D1R is of fundamental importance. Hence, the signal transduction pathways involved will be elucidated to test the hypothesis that amplification of cAMP accumulation is mediated by augmentation of G1s (derived from D1R coupling) stimulated adenylyl cyclase subtype-2 activity by 23 subunits liberated by GHS-R coupling to G1i. Specific Aims: 1.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; 2. Test the hypothesis that expression of GHS-R in D1R containing neurons provides a mechanism by which ghrelin protects neurons from oxidative damage by maintaining UCP2 expression; 3: Define the molecular mechanism of amplification of dopamine D1R-induced cAMP accumulation caused by co-activation of the ghrelin receptor (GHS-R): a.) signal transduction pathway; b.) stoichiometry of agonist and G-protein interaction with GHS-R homoligomers. These studies have near-term clinical applications because of the availability of orally active long-acting ghrelin mimetics shown to be safe and well tolerated.

描述（由申请人提供）：我们的目标是提供治疗性干预措施，以延长衰老期间的健康跨度。生长素素模拟MK-0677的发现是衰老研究中的一个里程碑发现。 MK-0677恢复了脆弱的老年人的生长激素（GH）轴，伴随着骨密度增加，瘦质量和强度。 MK-0677似乎营救了内源性生长素释放蛋白信号的年龄依赖性缺陷。证据继续出现以支持这一结论。除了恢复调节GH轴的神经元外，GHS-R（GHRELIN受体）还将其定位于调节情绪和认知功能的神经元。多巴胺受体亚型-1（D1R）在这些神经元中共表达，这意味着生长素蛋白是多巴胺信号传导的调节剂。体外研究支持了这一观念，并表明ghrelin通过形成GHS-R/D1R异二聚体来扩增多巴胺诱导的CAMP积累。因为通过增加神经元的cAMP积累来改善学习和记忆，因此通过选择性地增加具有生长素释放蛋白模拟物的D1R神经元的CAMP来挽救内源性生长素释放蛋白信号传导，这对老年人具有潜在的好处。 D1R信号的增强和GHS-R/D1R异二聚体的形成的假说将在体内发生，并且表现为行为效应，将使用ghrelin-/ - / - 和GHSR-/ - / - 小鼠进行测试。生长素素具有神经保护特性，是解偶联蛋白-2（UCP2）表达的阳性调节剂。 UCP2保护多巴胺神经元免受1-甲基-4-苯基-1,2,5,5,6四氢吡啶（MPTP）诱导的氧化损伤和死亡。因此，还将测试通过增加UCP2表达来阻止D1R神经元丧失的假设。 GHS-R和D1R之间的串扰导致cAMP产生的选择性神经元的扩增，而coxpress GHS-R和D1R具有基本意义。因此，将阐明所涉及的信号转导途径，以检验以下假设：cAMP积累的扩增是通过G1S的增强（从D1R偶联而得出的）刺激腺苷酸环化酶亚型-2刺激的23个亚基通过GHS-R耦合到G1I释放的23个亚基。具体目的：1。野生型，生长素蛋白 - / - 和生长素蛋白受体基因敲除小鼠（GHSR - / - ）的检验假设，即在体内发生生长素蛋白介导的扩增以增强D1R和GHS-R表达神经元的信号传导，从而在行为变化中表达神经元； 2。检验以下假设：含D1R神经元中GHS-R的表达提供了一种机制，通过维持UCP2的表达，生长素蛋白可以保护神经元免受氧化损伤； 3：定义多巴胺D1R诱导的cAMP积累的分子机制是由生长素受体（GHS-R）共激活引起的：A。）信号转导途径； b。）激动剂和G蛋白与GHS-R同源物的相互作用的化学计量法。这些研究具有近期的临床应用，因为表现为安全且耐受性良好的口服长效型生长素蛋白模拟物的可用性。