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

基本信息

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
项目类别：
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&apos 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

项目摘要

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，我在以下方面接受了广泛的培训：1）在我的硕士论文期间，女性性激素和行为的神经内分泌学； 2）博士论文期间应激反应的神经内分泌学和功能神经解剖学； 3）博士后培训期间的转化动物建模。该培训集中关注整个动物的生理学和行为，并结合使用微透析的体内神经化学测量；立体定向递送药理和通道追踪化合物，以及使用免疫组织化学进行离体功能性脑成像来检测立即早期基因蛋白。 2008年和2010年，我分别晋升为研究助理教授，然后晋升为精神病学系助理教授。在此期间，我发表了一篇第一作者《自然医学》文章，其中主要发现是下丘脑食欲素系统在公认的恐慌症大鼠模型中发挥着关键作用，并且恐慌症患者的中枢食欲素水平升高。我继续确定其他病理是否与过度活跃的食欲素系统有关。正是在这里，我在临床前研究中注意到雌激素会抑制食欲素活性，并且在最近的一项临床研究中，绝经期间雌激素的急剧减少导致中枢食欲素水平增加 300%，而雌激素替代可以逆转这种情况。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两种雌激素受体的下丘脑区域，导致我目前的假设：“食欲素系统在更年期相关症状（例如热）中发挥着关键作用。闪烁和情绪/睡眠中断”。潮热等不良更年期症状影响大约 70% 接近更年期的女性，北美更年期协会估计，每天有超过 6,000 名美国女性进入更年期。此外，50-64 岁的女性中有 63% 目前有工作（美国人口普查局，2003 年）。因此，不良更年期症状会导致工作日损失和医疗服务的直接医疗费用，从而对工作场所产生重大财务影响。这笔 K01 培训补助金代表了我职业生涯中一个重要但合乎逻辑的重定向，需要 IU 专家在以下方面提供额外的指导和培训：1）Daniel Rusyniak 医学博士进行的啮齿动物体温调节研究； 2）凯瑟琳·琼斯博士的性激素神经内分泌学； 3) 人类受试者中与更年期相关的“潮热”以及 Janet Carpenter 博士、注册护士、FAAN 教授的更年期课程； 4) Anantha Shekhar 博士/医学博士的转化研究方法和动物模型。我的培训还将包括由 Todd Skaar 博士针对目标 1 进行的药理学培训；由 IUSM 的 William Truitt 博士和 Kenneth Cornetta 医学博士针对目标 2 和 3 进行的分子生物学课程和培训； IUSM 的 Robert Bies 博士在目标 3b 中提供了昼夜节律分析培训。在博士的最初指导下。在 Rusyniak 和 Carpenter 的指导下，我于 2011 年获得了内部资助的 CTSI 项目开发补助金和转化研究领域的 KL-2 CTSI 青年研究员基础科学奖，以获得该补助金的初步数据。这里概述的目标和研究将有助于从“路线图”K 奖向“路线图”R 奖的过渡。我曾在2011年美国神经精神药理学学院和2012年转化科学会议上展示过初步结果，并分别被选为“Data Blitz”分会场的成员；并荣获学者摘要奖。我还在准备一份关于我们的“热潮红”漏洞新颖模型的手稿。这里概述的拟议研究具有创新性，原因如下：1）据我们所知，这是确定食欲素作用的首次尝试在更年期不良症状中。截至 2013 年 3 月，PubMed 搜索“食欲素”和“潮热”（这是更年期的主要症状）没有结果； 2) 这项拟议的研究基于有关雌激素对食欲素和受体生理学的调节、食欲素在睡眠觉醒周期中的作用的临床前信息，以及我们最近将过度活跃的食欲素系统与焦虑和体温失调联系起来的临床前和临床数据； 3）我们将进行动物研究，以阐明食欲素诱导更年期症状的机制，据我们所知，此前尚未有报道； 4）我开发了新的热潮红易感性动物模型来检验我的假设； 5）我将应用药理学、急性基因和慢性慢病毒siRNA基因沉默技术来了解其机制； 6）我将阐明调节潮热的神经机制，重点是下丘脑食欲素系统； 7) 我将提供机制研究，以制定转化临床方案，寻找食欲素受体拮抗剂的新用途，并提交 FDA 批准用于治疗失眠。我最近接受了 IUSM 解剖学与细胞生物学系的终身助理教授职位。我的实验室（湿实验室、手术区和生理学/行为室）位于 Truitt 博士的大厅对面，Rusyniak 博士的楼上一层，距离我的其他导师仅几步之遥，这使得这里成为理想的指导和协作环境。因此，这项培训资助的最终目标是帮助我成为一名独立调查员，广泛了解雌激素的急剧流失如何导致体温调节紊乱。这将使我能够为我们对导致潮热的神经和神经化学机制的了解做出重大贡献，并确定潜在的新型非激素治疗靶点。