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

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

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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）在我的论文硕士学位期间，女性性激素和行为的神经内分泌学； 2）在我的博士学位论文期间，压力反应的神经内分泌学和功能性神经解剖学； 3）在我的博士后培训期间翻译动物建模。该训练集体集中于整个动物的生理学和行为，并结合了使用微透析的体内神经化学测量。使用免疫组织化学检测早期基因蛋白的立体定位递送药理学和道追踪化合物以及离体功能性脑成像。在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的助理教授。在这段时间里，我发表了第一篇作者自然医学文章，其中主要发现是下丘脑奥列生酸蛋白系统在公认的恐慌症大鼠模型中起着至关重要的作用恐慌脆弱性，并且在恐慌症患者中，中枢Orexin水平升高。我继续确定其他病理是否与多活跃的Orexin系统相关联。在这里，我在临床前研究中指出，雌激素抑制了Orexin活性，而在更年期期间，最近的临床研究急剧损失导致Orexin中心水平增加了300％，而雌激素替代却逆转了。这一证据与奥甲蛋白在温度调节中的已知作用相结合，而Orexin System位于富含雌激素受体的下丘脑区域中，导致我目前的假设是“ Orexin System在更年期相关的症状中起着至关重要的作用，例如热闪光和情绪/睡眠破坏”。不良的更年期症状（例如潮热）会影响大约70％的接近更年期的女性，而北美绝经社会则认为，每天有6,000多名美国妇女到达更年期。此外，目前有63％的50-64岁妇女受雇（美国普查局，2003年）。因此，不良绝经症状通过损失的工作日和直接医疗服务的直接医疗服务对工作场所产生重大财务影响。这项K01培训补助金是我职业生涯中重大但逻辑的重定向，需要IU的专家在：1）丹尼尔·鲁斯尼亚克（Daniel Rusyniak）医学博士的啮齿动物体温调节研究中进行额外的指导和培训； 2）凯瑟琳·琼斯（Kathryn Jones Phd）的性激素神经内分泌学； 3）在人类学科中与更年期有关的“潮热”和由珍妮特·卡彭特（Janet Carpenter）博士教授的更年期课程； 4）MD/PhD Anantha Shekhar的翻译研究方法和动物建模。我的培训还将涉及托德·斯卡尔（Todd Skaar）博士的药理学培训。 William Truitt博士的分子生物学课程和培训和IUSM的Kenneth Cornetta医学博士为AIMS 2和3； Robert Bies博士在AIM 3B的Robert Bies PhD进行了昼夜节律分析中的培训。在Drs的最初指导下。 Rusyniak和Carpenter，我于2011年获得了内部资助的CTSI项目开发赠款和KL-2 CTSI年轻研究者基础科学奖，以获取该赠款的初步数据。此处概述的目的和研究将有助于从“路线图” K奖到“路线图” R奖。我在2011年的美国神经心理药理学学院和2012年的翻译科学会议上提出了初步结果，分别为“ Data Blitz”会议选出。并获得了学者的抽象奖。我还在我们的“热闪光”脆弱性的新型模型上准备手稿。由于以下原因，此处概述的拟议研究具有创新性：1）据我们所知，这是确定Orexin角色的首次尝试在不良绝经症状中。截至2013年3月，对主要更年期症状的PubMed搜索“ Orexin”和“ Hot Flash”均未产生任何结果； 2）这项提出的研究基于有关Orexin和受体生理学的雌激素调节，Orexin在睡眠唤醒周期中的作用以及我们最近的临床前和临床数据，将多活化的Orexin系统与焦虑和温度失调联系起来； 3）我们将进行动物研究，以阐明绝经症状诱导奥列海素诱导的机制，据我们所知，这尚未得到报道； 4）我已经开发了新颖的动物模型，以测试我的假设； 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该机制； 6）我将阐明调节炎热闪光的神经系统机制，重点是下丘脑Orexin System； 7）我将提供机械研究，该研究将导致一种转化临床方案，以发现提交FDA批准失眠的Orexin受体拮抗剂的新颖使用。我最近在IUSM接受了解剖学和细胞生物学系任职助理助理教授职位。我的实验室（一个湿lab，外科区域和生理/行为室）在Truitt博士的整个大厅对面，从Rusyniak博士靠近一层，并且在其他导师的步行范围内，使这是理想的指导和协作环境。因此，这是这项培训补助金的最终目标，可以帮助我成为一名独立的研究者，并对雌激素的戏剧性损失如何导致体温调节造成破坏。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标。