CALCITONIN GENE RELATED PEPTIDE AND AGING

降钙素基因相关肽与衰老

• 批准号: 6287169
• 负责人: PANDU R GANGULA
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287169
• 关键词: animal old age; biological models; blood pressure; calcitonin gene related peptide; estrogens; female; hormone regulation /control mechanism; hypertension; laboratory rat; ovariectomy; postmenopause; progesterone; vasodilation

Cardiovascular disease is the leading cause of death in the United States. Epidemiologic studies indicate that the morbidity of hypertension in women increases after menopause. Although hormonal replacement is the most useful therapy to reduce this disease, the mechanisms responsible for this disorder are not well understood. We propose that the calcitonin gene-related peptide (CGRP) plays a critical role in such mechanisms. CGRP, a potent vasodilator synthesized in dorsal root ganglia (DRG) neurons, is involved in the regulation of blood flow to vital organs. Reports indicate that alterations of CGRP may be involved in the pathophysio1ogy of a spectrum of cardiovascular diseases, including coronary artery disease and hypertension. Recently, we have employed ovariectomized (ovx; depletion of ovarian hormones) animals as a model of postmenopausal state in women in order to determine whether CGRP synthesis and vasodilator effects are decreased after ovariectomy in a steroid hormone-dependent fashion. Our results showed that the hypotensive effects of CGRP are enhanced by estrogen (E) and progesterone (P) in adult ovx rats. We further reported that both E and P stimulate neuronal expression of CGRP in a time- and dose-dependent manner in ovx rats. Furthermore, we found that circulating levels of CORP are significantly increased by female sex steroid hormones in adult ovx rats. These studies suggest that increased neuronal expression of CGRP by DRG may mediate, at least in part, the cardiovascular protective effects of sex hormones. In the present project, we will test this hypothesis in aged female rats in which steroid hormones, similarly to post-menopausal humans, decease with age. The goal of this proposal is to first determine whether neuronal expression of CORP and its hypotensive effects are altered in aged rats and to then determine the role played in this phenomenon by steroid hormones. These studies will provide evidence relevant to post menopausal aged women, where CORP may be an important factor mediating steroid hormone effects on blood pressure regulation. Furthermore, our preliminary studies indicate that circulatory levels of CGRP are significantly increased by 17beta-estradiol in aged rats after long-term ovariectomy. We also wish to extend these studies to ovariectomized aged rats in order to determine whether the perturbations in vasodilatory effects of CGRP are modulated by steroid hormone rep1acement treatment. These studies are important for the assessing whether increased levels of CGRP by steroid hormones play a role in decreasing cardiovascular disorders that are typical of aged women after several years of menopause.

心血管疾病是美国人死亡的主要原因。流行病学研究表明，绝经后妇女高血压的发病率增加。虽然激素替代疗法是减少这种疾病的最有用的疗法，但对这种疾病的机制还不清楚。我们认为降钙素基因相关肽（CGRP）在这种机制中起着至关重要的作用。CGRP是在背根神经节（DRG）神经元中合成的一种有效的血管扩张剂，参与调节重要器官的血流。有报道表明CGRP的改变可能参与一系列心血管疾病的病理生理，包括冠状动脉疾病和高血压。最近，我们采用卵巢切除（卵巢激素耗竭）动物作为绝经后妇女状态的模型，以确定是否CGRP合成和血管舒张作用在卵巢切除术后类固醇激素依赖性方式减少。结果表明，雌激素（E）和孕激素（P）可增强CGRP对成年OVX大鼠的促排卵作用。我们进一步报道，E和P刺激神经元CGRP的表达在一个时间和剂量依赖性的方式在ovx大鼠。此外，我们发现，循环水平的CORP显着增加雌性类固醇激素在成年OVX大鼠。这些研究表明，DRG神经元CGRP表达增加可能介导，至少部分介导性激素的心血管保护作用。在本项目中，我们将在老年雌性大鼠中测试这一假设，其中类固醇激素与绝经后的人类相似，随着年龄的增长而下降。这项建议的目的是首先确定是否神经元表达的CORP和其肿胀的影响是改变老年大鼠，然后确定类固醇激素在这种现象中发挥的作用。这些研究将为绝经后老年妇女提供相关证据，其中CORP可能是介导类固醇激素对血压调节作用的重要因素。此外，我们的初步研究表明，循环中的CGRP水平显着增加17 β-雌二醇在老年大鼠长期卵巢切除术后。我们还希望将这些研究扩展到卵巢切除的老年大鼠，以确定CGRP的血管舒张作用的扰动是否受到类固醇激素替代治疗的调节。这些研究对于评估类固醇激素引起的CGRP水平升高是否在减少绝经数年后老年妇女典型的心血管疾病中发挥作用非常重要。

项目成果

N6-Isopentenyladenosine Impairs Mitochondrial Metabolism through Inhibition of EGFR Translocation on Mitochondria in Glioblastoma Cells.

• DOI: 10.3390/cancers14246044
• 发表时间: 2022-12-08
• 期刊: Cancers
• 影响因子: 5.2

Impacts of Environmental Pollution on Brain Tumorigenesis.

• DOI: 10.3390/ijms24055045
• 发表时间: 2023-03-06
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Pagano, Cristina;Navarra, Giovanna;Coppola, Laura;Savarese, Beatrice;Avilia, Giorgio;Giarra, Antonella;Pagano, Giovanni;Marano, Alessandra;Trifuoggi, Marco;Bifulco, Maurizio;Laezza, Chiara
• 通讯作者: Laezza, Chiara

Age-related changes in dorsal root ganglia, circulating and vascular calcitonin gene-related peptide (CGRP) concentrations in female rats: effect of female sex steroid hormones.

• DOI: 10.1016/j.neulet.2009.02.068
• 发表时间: 2009-04-24
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Gangula PR;Chauhan M;Reed L;Yallampalli C
• 通讯作者: Yallampalli C