Hypothalamic Orexin Role in Menopause-Associated Hot Flashes and Mood/Sleep Disru

下丘脑食欲素在更年期相关潮热和情绪/睡眠障碍中的作用

• 批准号: 8635599
• 负责人: Philip Lee Johnson
• 金额: $ 11.68万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635599
• 关键词: Acute; Adverse effects; Affect; Age; Age-Years; American; Anatomy; Animal Model; Animals; Anxiety; Area; Attenuated; Award; Basic Science; Behavior; Behavioral; Body Temperature; Brain imaging; Cancer Etiology; Cellular biology; Censuses; Cerebrospinal Fluid; Cessation of life; Chronic; Circadian Rhythms; Clinical Data; Clinical Protocols; Clinical Research; Coronary heart disease; Cutaneous; Data; Desire for food; Development; Doctor of Philosophy; Educational process of instructing; Estrogen Receptors; Estrogen Replacement Therapy; Estrogen Replacements; Estrogens; Female; Floor; Funding; Gases; Gene Proteins; Gene Silencing; Genes; Goals; Gonadal Steroid Hormones; Grant; Health; Health Care Costs; Hot flushes; Human; Hypothalamic structure; Immediate-Early Genes; Immunohistochemistry; Incidence; K-Series Research Career Programs; Laboratories; Lead; Lesion; Link; Manuscripts; Measures; Medical; Medicine; Menopausal Symptom; Menopause; Mentors; Mentorship; Microdialysis; Modeling; Molecular Biology; Moods; Motor Activity; Mus; Nature; Neuroanatomy; Neuroendocrinology; Neurologic; Neurons; Operative Surgical Procedures; Ovariectomy; Panic; Panic Disorder; Pathology; Patients; Pattern; Peripheral; Pharmacology; Phase III Clinical Trials; Physiologic Thermoregulation; Physiology; Play; Positioning Attribute; Production; Psychiatry; PubMed; Publishing; Rattus; Regulation; Reporting; Research; Research Personnel; Risk; Rodent; Role; Services; Sex Behavior; Sleep; Sleep Wake Cycle; Sleep disturbances; Sleeplessness; Small Interfering RNA; Societies; Stimulus; Stroke; Surgical Models; Symptoms; System; Tail; Techniques; Temperature; Testing; Thromboembolism; Time; Training; Translational Research; Vasodilation; Venous; Walking; Woman; Women' s Health; Work; Workplace; abstracting; base; biological adaptation to stress; career; college; disturbance in affect; effective therapy; human subject; hypocretin; in vivo; indium arsenide; innovation; malignant breast neoplasm; meetings; neurochemistry; novel; post-doctoral training; pre-clinical; preclinical study; prevent; professor; receptor; relating to nervous system; reproductive; response; small hairpin RNA

DESCRIPTION (provided by applicant): Currently I have had extensive training in: 1) neuroendocrinology of female sex hormones and behavior during my Masters with Thesis; 2) neuroendocrinology and functional neuroanatomy of stress responses during my PhD dissertation; and 3) translational animal modeling during my postdoctoral training. This training was collectively focused on whole animal physiology and behavior, combined with in vivo neurochemistry measures using microdialysis; stereotaxic delivery of pharmacological and tract tracing compounds, and ex vivo functional brain imaging using immunohistochemistry to detect immediate early gene proteins. In 2008 and 2010, I was respectively promoted to Research Assistant Professor, and then to Assistant Professor in the Department of Psychiatry. During this time I published a 1st author Nature Medicine article, where the main discovery was that a hypothalamic orexin system plays a critical role panic vulnerability in an accepted rat model of panic disorder and that central orexin levels are elevated in patients with panic disorder. I proceeded to determine if other pathologies were associated with a hyperactive orexin system. It was here that I noted in preclinical studies that estrogens suppress orexin activity and that ina recent clinical study dramatic loss of estrogen during menopause leads to a 300% increase in central levels of orexin, which was reversed with estrogen replacement. This evidence, combined with orexin's known role in thermoregulation, and that the orexin system is located in a hypothalamic area enriched in both estrogen receptors, led to my current hypothesis that "the orexin system plays a critical role in menopause-related symptoms such as hot flashes, and mood/sleep disruption". Adverse menopausal symptoms such as hot flashes affect about 70% of women approaching menopause and The North American Menopause Society posits that over 6,000 American women reach menopause daily. In addition, 63% of women ages 50-64 years are currently employed (U.S. Bureau of the Census, 2003). Thus, adverse menopausal symptoms have a significant financial impact in the workplace through lost work days and direct health care costs for medical services. This K01 training grant represents a significant, but logical, redirection in my career that requires additional mentoring and training by experts at IU in: 1) rodent studies in thermoregulation by Daniel Rusyniak MD; 2) sex hormone neuroendocrinology by Kathryn Jones PhD; 3) menopause-related "hot flashes" in human subjects and a Menopause course taught by Janet Carpenter, PhD, RN, FAAN; and 4) translational research approaches and animal modeling by Anantha Shekhar, MD/PhD. My training will also involve pharmacology training by Todd Skaar PhD for aim 1; molecular biology coursework and training by William Truitt, PhD, and Kenneth Cornetta MD at IUSM for aims 2 and 3; and training in circadian analyses by Robert Bies PhD at IUSM in aim 3b. Under the initial mentorship of Drs. Rusyniak and Carpenter, I have obtained an internally funded CTSI project development grant and a KL-2 CTSI Young Investigator Basic Science Award in Translational Research in 2011 to gain preliminary data for this grant. The aims and studies outlined here will aid in the transition from a 'Roadmap' K award to 'Roadmap' R awards. I have presented preliminary results at the American College of Neuropsychopharmacology in 2011 and at the Translational Science meeting in 2012, where I was respectively selected for the "Data Blitz" session; and won a Scholar's Abstract Award. I am also preparing a manuscript on our novel models of "hot flash" vulnerability. The proposed research outlined here is innovative for the following reasons: 1) to our knowledge this is the first attempt to determine orexin's role in adverse menopausal symptoms. A PubMed search for "orexin" and "hot flash" which is the primary menopause symptom yields no results as of March 2013; 2) this proposed research is based on preclinical information about estrogen regulation of orexin and receptor physiology, orexin's role in sleep wakes cycles, and our recent preclinical and clinical data linking a hyperactive orexin system to anxiety and temperature dysregulation; 3) we will conduct animal studies to elucidate the mechanisms underlying orexin induction of menopausal symptoms, which to our knowledge, has not been previously reported; 4) I have developed novel animal models of hot flash vulnerability to test my hypotheses; 5) I will apply pharmacology, acute gene and chronic lentiviral siRNA gene silencing techniques to understand the mechanism; 6) I will elucidate the neurologic mechanisms that regulate hot flashes with emphasis on the hypothalamic orexin system; and 7) I will provide mechanistic studies that will lead to a translational clinical protocol finding a novel use of an orexin receptor antagonist submitted for FDA approval for insomnia. I recently accepted a tenure track Assistant Professor position in the Department of Anatomy & Cell Biology at IUSM. My laboratory (a wetlab, surgical area and physiology/behavior room) is across the hall from Dr. Truitt and one floor up from Dr. Rusyniak, and within walking distance of my other mentors, making this an ideal mentoring and collaborative setting. Therefore, it is the ultimate goal of this training grant to help me become an independent investigator with an extensive understanding of how dramatic loss of estrogens lead to disrupted thermoregulation. This will allow me to make significant contributions to our knowledge of the neural and neurochemical mechanisms that lead to hot flashes and to identify potential novel nonhormonal targets for treatment.

描述（由申请人提供）：目前，我在硕士论文期间接受了广泛的培训：1)女性性激素和行为神经内分泌学；2)博士论文神经内分泌学和应激反应功能神经解剖学；3)在我的博士后训练期间，翻译动物模型。该训练集中在整个动物的生理和行为上，并结合使用微透析的体内神经化学测量；立体定向递送药物和通道示踪化合物，以及使用免疫组织化学检测早期基因蛋白的离体功能脑成像。2008年和2010年分别晋升为研究助理教授和精神病学助理教授。在此期间，我以第一作者身份发表了一篇《自然医学》（Nature Medicine）文章，主要发现是下丘脑食欲素系统在一个公认的恐慌障碍大鼠模型中的恐慌脆弱性中起着至关重要的作用，并且恐慌障碍患者的中枢食欲素水平升高。我继续确定是否有其他病理与过度活跃的食欲素系统有关。正是在这里，我注意到在临床前研究中，雌激素抑制食欲素的活性，在最近的临床研究中，绝经期间雌激素的急剧减少会导致食欲素中枢水平增加300%，而雌激素替代会逆转这种情况。这一证据，再加上食欲素在体温调节中的已知作用，以及食欲素系统位于富含雌激素受体的下丘脑区域，导致了我目前的假设，即“食欲素系统在更年期相关症状（如潮热、情绪/睡眠中断）中起着关键作用”。大约70%接近更年期的女性会受到潮热等更年期不良症状的影响，北美更年期协会（North American menopause Society）认为，每天有超过6000名美国女性进入更年期。此外，63%的50-64岁女性目前有工作（美国人口普查局，2003年）。因此，不利的更年期症状对工作场所产生了重大的经济影响，损失了工作日和医疗服务的直接保健费用。这项K01培训补助金代表了我职业生涯中一个重要的，但合乎逻辑的重定向，需要IU专家在以下方面的额外指导和培训：1)Daniel Rusyniak博士的体温调节啮齿动物研究；2) Kathryn Jones博士性激素神经内分泌学；3)人类受试者与更年期相关的“潮热”和Janet Carpenter，博士，注册护士，FAAN教授的更年期课程；4) Anantha Shekhar（医学博士/博士）的转化研究方法和动物模型。我的培训还包括目标1的药理学培训，由Todd Skaar博士指导；威廉·特鲁伊特博士和肯尼斯·科内塔医学博士的分子生物学课程和培训，目标2和目标3；以及由美国国立农业大学Robert Bies博士在aim 3b进行的昼夜节律分析培训。在博士最初的指导下。Rusyniak和Carpenter，我已经获得了内部资助的CTSI项目发展资助和2011年的KL-2 CTSI青年研究员转化研究基础科学奖，以获得这项资助的初步数据。这里概述的目标和研究将有助于从“路线图”K奖过渡到“路线图”R奖。在2011年的美国神经精神药理学学院和2012年的转化科学会议上，我分别被选为“数据闪电战”会议的初步结果；并获得了学者摘要奖。我还在准备一份关于我们的“潮热”脆弱性新模型的手稿。这里提出的研究是创新的，原因如下：1)据我们所知，这是第一次尝试确定食欲素的作用