CALCITONIN GENE RELATED PEPTIDE AND AGING

降钙素基因相关肽与衰老

基本信息

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
项目类别：
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

项目摘要

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.

心血管疾病是美国死亡的主要原因。流行病学研究表明，更年期后女性高血压的发病率增加。尽管荷尔蒙替代是降低这种疾病的最有用的疗法，但对这种疾病的机制却尚不清楚。我们建议降钙素基因相关的肽（CGRP）在这种机制中起关键作用。 CGRP是一种在背根神经（DRG）神经元中合成的有效血管扩张剂，参与了血液流向重要器官的调节。报告表明，CGRP的改变可能与多种心血管疾病（包括冠状动脉疾病和高血压）的病理生理学有关。最近，我们采用了卵巢切除术（OVX；卵巢激素的耗竭）作为女性绝经后状态的模型，以确定在类固醇荷尔蒙依赖性依赖类固醇激素的方式中，卵巢切除术后CGRP合成和血管扩张作用是否降低。我们的结果表明，成年OVX大鼠的雌激素（E）和孕酮（P）增强了CGRP的降压作用。我们进一步报道，E和P均以OVX大鼠的时间和剂量依赖性方式刺激CGRP的神经元表达。此外，我们发现成年OVX大鼠的女性性类固醇激素的循环水平显着增加。这些研究表明，DRG的CGRP神经元表达的增加至少可能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检验这一假设，其中类固醇激素（类似于绝经后人类）随着年龄的增长而衰落。该提案的目的是首先确定CORP的神经元表达及其降压作用在老年大鼠中是否会改变，然后确定类固醇激素在这种现象中所起的作用。这些研究将提供与更年期老年妇女有关的证据，在这种情况下，Corp可能是介导类固醇激素对血压调节的影响的重要因素。此外，我们的初步研究表明，长期卵巢切除术后，老年大鼠的循环水平被17beta-雌二醇显着增加。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血管舒张作用的扰动是否通过类固醇激素rep1摄取治疗调节。这些研究对于评估类固醇激素增加的CGRP水平是否在减少经过几年更年期后老年妇女的典型心血管疾病中发挥作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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