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.

Public Health Relevance

Although estrogen replacement therapy was the first line treatment for menopausal symptoms such as hot flashes and mood disruption, the Women's Health Initiative study determined that extended use leads to the development of breast cancer, and coronary heart disease etc. Therefore, there is a need for non-hormonal therapies to reduce the incidence of adverse menopausal symptoms. Here we will use pharmacologically and genetically inhibit a nonhormone orexin hypothalamic system that regulates temperature and mood, and is hyperactive during menopause.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
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Mackiewicz, Miroslaw
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Indiana University-Purdue University at Indianapolis
Anatomy/Cell Biology
Schools of Medicine
United States
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Johnson, Philip L; Federici, Lauren M; Shekhar, Anantha (2014) Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks. Neurosci Biobehav Rev 46 Pt 3:429-54