2016 — 2020 |
Xu, Pingwen |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Medial Amygdala Er? Neurocircuits in the Regulation of Physical Activity @ University of Illinois At Chicago
? DESCRIPTION (provided by applicant): The current application aims to map the medial amygdala (MeA) estrogen receptor alpha (ER?) neurocircuits that are essential for physical activity and body weight control. Our studies will not only advance our current understanding about the physical activity control and the development of obesity in general but also identify new feasible intervention targets for the development of novel therapeutic approaches to combat sedentary behaviors. Therefore, this proposed research is directly relevant to public health and the NIH's mission. I have four years of postdoctoral research experience when submitting this application (07/2011-07/2015). My long- term goal is to establish myself as an independent investigator in the area of central regulation of physical activity and metabolism. In order to develop an independent researcher in this field, I will use my K99-funded mentored period to (1) gain new training in exercise physiology to compare different aspects of treadmill exercise and voluntary wheel running behavior in mouse model; (2) implement the most advanced knowledge about physical activity/metabolism and cutting-edge techniques in the field of central regulation of metabolic behavior; (3) advance grantsmanship, project and laboratory management skills, mentoring, teaching skills, etc. I will start looking for university faculty positions towards the end of the first year of the K99 stage to ensure the smooth transition to the R00 phase. The ovary hormone, estrogen, plays an important role in maintaining normal energy homeostasis by regulating food intake and physical activity. While ER? expressed by pro-opiomelanocortin (POMC) in the hypothalamic arcuate nucleus (ARC) modulates food intake, estrogen- responsive neurons influencing locomotion remain undefined. Recently, we demonstrated that ER? expressed by the Single Minded 1 (SIM1) neurons in the MeA dedicated to promoting locomotion in both males and females. Additionally, acute activation of MeA SIM1 neurons led to short term increase of locomotion. These suggest that ER? expressed by MeA SIM1 neurons constitute part of a previously undefined locomotor circuit that is used in both males and females. Here, we plan to further define and understand how this MeA estrogen- responsive neural circuit promotes locomotion. In the aim 1 and 2 (K99 phase), we will (1) test if ER? in the MeA is required for the coordinated control of locomotor activity, body weight and exercise-induced metabolic benefits by using mouse/virus genetic loss-of-function and gain-of-function models to specifically delete or overexpress whole ER? population in the MeA; (2) further demonstrate if activation/inhibition of MeA ER? neurons increases/decreases locomotion by using a novel technology termed Designer Receptors Exclusively Activated by Designer Drugs (DREADD). With this information in hand, we will then start aim 3 (R00 phase) to map the downstream neural circuits of MeA ER? neurons and identify the critical MeA downstream neural circuits where estrogen acts to stimulate locomotion and prevent obesity. The proposed studies represent logical extensions to our previous work and offer an excellent opportunity to understand the neural basis of estrogenic regulation of locomotion, not only in females but also in males.
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2021 |
Xu, Pingwen |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Testosterone and Estrogen Signaling Pathways in the Medial Amygdala Interact to Control Energy Homeostasis @ University of Illinois At Chicago
Sex steroids, including estrogens and androgens, play an important role in regulating energy homeostasis. Brain sex steroid signaling is required for normal body weight maintenance. We previously showed that estrogen receptor ? (ER?) neurons in the medial amygdala (MeA) stimulate physical activity and energy expenditure to decrease body weight in both males and females. It suggests that the estrogen/ER?MeA circuit constitutes part of a previously undefined brain metabolic signaling in both males and females. Interestingly, the MeA has high levels of other three key components of testosterone/estrogen signaling, including an essential enzyme for estrogen synthesis (aromatase; Aro), and key mediating receptors for testosterone/estrogen signaling (androgen receptor, estrogen receptor ? and ?; AR, ER? and ER?). These data raise the possibility that circulating testosterone directly binds to AR or is aromatized by Aro to estradiol, which then binds to ER? or ER? to exert metabolic functions. We hypothesize that the neurosteroid testosterone/estrogen signaling pathways in the MeA interact to maintain normal energy homeostasis. To test this, three mutant mice will be generated to have each of these three components deleted specifically in the MeA neurons, respectively. These mouse strains (both males and females) will be used to determine the physiological roles of these three components in maintaining energy homeostasis in different sexes. The functional interactions between these components and the sex hormones will also be examined. Results from these studies will advance our current understanding of body weight control and the development of obesity in general. Further, our studies may narrow down the brain regions and hormone/receptors that are critical for the regulation of energy balance, which may serve as targets for the development of new anti-obesity strategies.
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