Establishment of a primate model for menopausal hot flushes

灵长类动物更年期潮热模型的建立

• 批准号: 9262118
• 负责人: ISTVAN Jozsef MERCHENTHALER
• 金额: $ 18.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9262118
• 关键词: Adult; Adverse effects; Affect; Aging; Animal Model; Animals; Anxiety; Behavior; Blood - brain barrier anatomy; Body part; Brain; Breast; Cardiovascular Diseases; Data; Development; Devices; Elderly man; Elderly woman; Ensure; Estradiol; Estrogen Therapy; Estrogens; Face; Flushing; Genitourinary system; Goals; Gonadal Steroid Hormones; Hormonal; Hormonal Change; Hot flushes; Human; Hydroquinones; Image; Implant; Incidence; Life; Link; Longevity; Macaca mulatta; Measurement; Measures; Menopausal Symptom; Menopause; Mental Depression; Methodology; Modeling; Monitor; Monkeys; Moods; Norepinephrine; Organ; Osteoporosis; Ovariectomy; Oxidoreductase; Pattern; Peripheral; Postmenopause; Prevention; Primates; Process; Prodrugs; Progestins; Quality of life; Rattus; Reading; Research; Selective Serotonin Reuptake Inhibitor; Serotonin; Site; Skin; Skin Temperature; Sleep Disorders; Study models; Subcutaneous Tissue; Surface; Sweat; Sweating; Symptoms; Tail; Technology; Telemetry; Temperature; Testing; Training; Uterus; Vasodilation; Water; Woman; cancer risk; cognitive function; cost; effective therapy; estrogenic activity; experience; face skin; gabapentin; hormone therapy; inhibitor/antagonist; innovation; juvenile animal; nonhuman primate; novel; novel therapeutics; prevent; public health relevance; response; reuptake; soy; subcutaneous; success

 DESCRIPTION (provided by applicant): Menopause is an inevitable consequence of aging in women, and it affects the quality of life of millions of women all over the world. Menopausal symptoms including hot flushes, a decline in cognitive function, sleep disorders, depression/anxiety, cardiovascular disease, genitourinary conditions, and osteoporosis. These symptoms have been shown to be causally linked to a decline in circulating sex steroid concentrations, which is particularly dramatic after menopause. Consequently, menopausal symptoms are considerably more problematic in elderly women than in elderly men. The most immediate and unbearable symptoms of the menopause are hot flushes, which cause not only physical discomfort but also negatively impact mood and behavior and in general, the quality of life. Among current treatments of hot flushes, only estrogen therapy and hormone therapy (estrogens and progestins have satisfactory efficacies. Although estrogens prevent hot flashes, they have unwanted side effects in the periphery, including the stimulation of the uterus and breast, and the increased risk of cancer risk in these organs. Although there has been a great effort to develop safer estrogens, the lack of animal model(s) reminiscent for the symptoms, their pathomechanism, temporal pattern, etc. of women's menopause has had a tremendous negative impact on the success of this effort. We have recently shown that nonhuman primates, such as the rhesus macaque, undergo a menopausal process that is hormonally identical to that of women. They, therefore, hold great promise for studies aimed at elucidating the mechanisms that underlie hot flushes in women, and for the development of safe and effective therapies. Although the use of NHPs for studies aimed at developing novel treatments for menopausal symptoms is critical, due to high costs and technical problems, there have been only two studies utilizing them in the last 30 years. This proposal has been written in response to PA-13-156: "Development and characterization of animal models for aging research (R21)". We propose to develop a novel, non-invasive NHP model of hot flush, using novel non-invasive technology. Specifically, our primary goal here is to evaluate a primate model of hot flush, by examining the effects of ovariectomy and subsequent treatment with estrogen, on adult rhesus monkey facial skin temperature, using infrared thermal imaging (FLIR T650sc) without restraining the animals. Once the monkey hot flush model is established and the new non-invasive thermal imaging methodologies validated, we intend to submit a new R01 application to evaluate our novel and innovative approach to treat menopausal hot flushes with a brain-selective estrogen which would not have side effects in peripheral organs such as the uterus and breast.

 更年期是女性衰老的必然结果，它影响着全世界数百万女性的生活质量。月经症状包括潮热、认知功能下降、睡眠障碍、抑郁/焦虑、心血管疾病、泌尿生殖系统疾病和骨质疏松症。这些症状已被证明与循环性类固醇浓度下降有因果关系，这在绝经后尤其明显。因此，更年期症状在老年女性中比在老年男性中更成问题。更年期最直接和最难以忍受的症状是潮热，这不仅会导致身体不适，而且会对情绪和行为以及一般生活质量产生负面影响。在目前治疗潮热的方法中，只有雌激素治疗和激素治疗（雌激素和孕激素）具有令人满意的疗效。虽然雌激素可以预防潮热，但它们在外周有不必要的副作用，包括刺激子宫和乳房，以及增加这些器官患癌症的风险。尽管已经做出了很大的努力来开发更安全的雌激素，但缺乏能让人联想到妇女更年期症状、其病理机制、时间模式等的动物模型，这对这种努力的成功产生了巨大的负面影响。我们最近发现，非人类灵长类动物，如恒河猴，经历的更年期过程与女性的更年期过程相同。因此，它们对旨在阐明女性潮热机制的研究以及开发安全有效的治疗方法具有很大的希望。虽然使用NHP进行旨在开发绝经期症状新疗法的研究至关重要，但由于成本高和技术问题，在过去30年中只有两项研究使用它们。本提案是根据PA-13-156：“衰老研究动物模型的开发和表征（R21）”编写的。我们建议开发一种新的，非侵入性的NHP模型的潮热，使用新的非侵入性技术。具体来说，我们的主要目标是评估一个灵长类动物模型的潮热，通过检查卵巢切除术和随后的治疗雌激素，对成年恒河猴面部皮肤温度的影响，使用红外热成像（FLIR T650 sc），而不限制动物。一旦猴子潮热模型建立和新的非侵入性热成像方法验证，我们打算提交一个新的R 01申请，以评估我们的新的和创新的方法来治疗更年期潮热与脑选择性雌激素，不会有副作用，在外周器官，如子宫和乳房。