2010 — 2011 |
Walker, Deena M. |
F31Activity Code Description: To provide predoctoral individuals with supervised research training in specified health and health-related areas leading toward the research degree (e.g., Ph.D.). |
Epigenetic Molecular Mechanisms and Reproductive Transitions @ University of Texas, Austin
DESCRIPTION (provided by applicant): The ability of an organism to attain and maintain reproductive competence involves the intricate coordination of a suite of hypothalamic genes that must be turned on/off in coordination with the life stage and the environment. Among those factors regulating reproductive neuroendocrine gene expression are circulating sex steroid hormones, including estradiol. While sex hormones are required to modulate reproductive life transitions in both an age- and sex-dependent manner, their underlying mechanisms are not well understood. This proposal focuses on elucidating the epigenetic molecular mechanisms by which an organism's hormonal environment modulates its hypothalamic gene expression to ensure the coordination of proper reproductive physiology with life stage. The focus will be the estrogen receptor alpha (ER1) and kisspeptin, chosen because these hypothalamic genes are expressed in a sexually dimorphic manner, they undergo robust changes across the life cycle, and because exogenous estrogen exposure during early life development perturbs their gene expression and disrupts reproductive development and aging. Aim 1 will test whether the epigenetic modification of DNA methylation affects the programming of ER1 and kisspeptin gene expression in hypothalamic regions. Aim 2 will test the hypothesis that the epigenetic event of histone acetylation is important for the activation and maintenance of the expression of these genes in adulthood, and during the process of reproductive senescence. Experiments will be carried out in male and female rats, making comparisons by sex and age. A subset of animals will be exposed to prenatal estradiol, which disrupts reproductive processes and hastens reproductive aging. As a whole, these studies will provide novel epigenetic molecular data on the organization and maintenance of key hypothalamic genes required for proper reproductive function and further illuminates the link between gene expression and the hormonal environment. PUBLIC HEALTH RELEVANCE: The proposed experiments in rats are highly relevant to human health because the hormones and physiology of reproduction are highly conserved. These studies are particularly important for understanding the loss of reproductive function as a model for menopause (women) /"andropause" (men). Although they are not diseases, these life transitions are associated with considerably elevated risk for cardiovascular disease, breast, prostate and uterine cancer, metabolic disorders and osteoporosis, all of which are hormone- dependent. Additionally, these life changes are associated with central nervous system problems including hot flashes, sleep deprivation, depression and anxiety. Therefore, a better understanding of the neural molecular mechanisms regulating these events could prove beneficial to promoting healthy aging.
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1 |
2018 — 2021 |
Walker, Deena M. |
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. |
A Novel Role For the Medial Amygdala in the Modulation of Sex Differences in Cocaine Reward @ Icahn School of Medicine At Mount Sinai
PROJECT SUMMARY/ABSTRACT Sex differences in the propensity to develop substance use disorders (SUD) are well established, but research to determine the mechanistic underpinnings remains sparse. In recent years, the number of women with SUD has markedly increased and the number of adolescent girls using stimulants has exceeded that of boys. Given that females are more sensitive to drugs of abuse, develop SUD more quickly, find it more difficult to quit once addicted, suffer greater withdrawal symptoms and exhibit shorter times of abstinence before relapse, this demographic shift in drug taking behaviors represents a public health crisis. Addiction is a medical, social and economic burden with few treatment options and none that are sex-specific. Therefore, it is imperative to understand the pathophysiology of addiction and how best to manage it, in men and women. In my career, I will build an independent research program that investigates and clarifies the cellular, molecular and circuit specific mechanisms of sex differences in drug addiction. This proposal will investigate the role of the medial amygdala (meAMY), a known sexually dimorphic region, in modulating sex differences in cocaine self-administration (SA). This Pathway to Independence Award will provide the opportunity to build on my expertise in sexual differentiation of the brain and cellular/molecular neuroscience while simultaneously developing my training in behavioral pharmacology and in vivo imaging and manipulation of circuit activity. In the mentored (K99) portion of this award, I will focus on characterizing sex differences in meAMY activity and its modulation of reward through sex-specific inputs to the ventral tegmental area (VTA). Under the mentorship of Drs. Eric Nestler and Veronica Alvarez, I will investigate how meAMY cellular activity is temporally associated with sexually dimorphic SA behaviors using fiber photometry to measure in vivo Ca2+ flux. This cutting-edge and powerful technique can probe meAMY cellular activity in a real-time during acquisition of cocaine SA, a sexually dimorphic behavior. With additional mentorship from Dr. Paul Kenny, I will study the functionality of sex differences in connectivity of the meAMY to VTA by chemogenetically inhibiting sex-specific meAMY ? VTA projections in males to reverse/reduce sex difference in SA acquisition. These experiments will prepare me to functionally interrogate the role of the meAMY as a mediator of sex differences in reward throughout mesolimbic dopamine pathways in the R00 portion of this award. My independent laboratory will investigate meAMY sex differences in modulation of glutamatergic inputs to the nucleus accumbens (NAc) during operant SA and characterize the role of these inputs in sexually dimorphic drug-seeking behaviors. In sum, the research proposed in this Pathway to Independence Award will reveal both separate and potentially interactive cellular and circuit-wide mechanisms underlying sex differences in addiction and drug abuse. More broadly, the added training afforded by this award will prepare me to launch an independent research program evaluating sex differences in reward, from molecules to circuitry, in a translational model of drug abuse.
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0.939 |