Research pertaining to this grant has evolved toward determining the role of microglia in mediating ethanol apoptotic action on developing ?-endorphin neurons involved in regulation of the hypothalamic pituitary adrenal axis (HPA) functions. The work conducted by us during the past funding period of the MERIT award demonstrated that alcohol exposure during early life causes activation of microglial cells and releases cytokines and chemokines that impact the physiological functions of hypothalamic neurons. Furthermore, early life exposure of ethanol may program the microglial cell population to produce more inflammatory cytokines following a stress challenge in the adulthood. Also, ?-endorphin neurons that regulate the HPA axis are not only a target of inflammatory cytokines and chemokines but also a modulator of microglial cell functions. Given the lack of information how microglia and BEP interact to control stress responses and the availability of methods of culturing pure ?-endorphin neurons from rat neuronal stem cells, we propose to test the following hypotheses: i) alcohol exposures stimulate microglia to produce inflammatory cytokines including TNF-? that activates the nuclear factor-?B (NF?B) pathway and NADPH oxidase to induce apoptotic signaling in developing ?-endorphin neurons; ii) ?-endorphin neurons influences the ethanol's ability to increase inflammatory cytokines production by altering opioid receptor functions in microglial cells; and iii) early-life alcohol exposures program the microglial cell population to produce more inflammatory cytokines following a stress challenge during the adulthood. We will employ various state-of-the art techniques involving in vitro differentiated pure ?-endorphin cells, primary cultures of microglial cells, neonatal model of alcohol feeding, microarray and proteomic approaches, western blot, realtime PCR, MeDIP assay, double immunocytochemistry, gene knocking-down. We will also use both in vitro and in vivo approaches. We anticipate these studies will identify whether a bi-directional communication between microglia and B-endorphin within the hypothalamus may predict risk for stress abnormality in a model of developmental alcohol exposures.
The proposed series of studies should continue to generate valuable data for better understanding of ethanol's neurotoxic action on developing ?-endorphin neurons. Additionally, the proposed research should identify compounds acting on novel targets to inhibit the release of a wide range of proinflammatory factors from overactivated microglia that might be critical for preventing of ?-endorphin neuronal death.
|Shrivastava, Pallavi; Cabrera, Miguel A; Chastain, Lucy G et al. (2017) Mu-opioid receptor and delta-opioid receptor differentially regulate microglial inflammatory response to control proopiomelanocortin neuronal apoptosis in the hypothalamus: effects of neonatal alcohol. J Neuroinflammation 14:83|
|Chastain, Lucy G; Sarkar, Dipak K (2017) Alcohol effects on the epigenome in the germline: Role in the inheritance of alcohol-related pathology. Alcohol 60:53-66|
|Rachdaoui, Nadia; Sarkar, Dipak K (2017) Pathophysiology of the Effects of Alcohol Abuse on the Endocrine System. Alcohol Res 38:255-276|
|Murugan, Sengottuvelan; Dave, Yatee; Rakhit, Ankush et al. (2017) Hypothalamic beta-endorphin neurons suppress preneoplastic and neoplastic lesions development in 1,2-dimethylhydrazine induced rat colon cancer model. J Cancer 8:3105-3113|
|Rachdaoui, Nadia; Li, Ling; Willard, Belinda et al. (2017) Turnover of histones and histone variants in postnatal rat brain: effects of alcohol exposure. Clin Epigenetics 9:117|
|Sarkar, Dipak K (2016) Male germline transmits fetal alcohol epigenetic marks for multiple generations: a review. Addict Biol 21:23-34|
|Zhang, Changqing; Franklin, Tina; Sarkar, Dipak K (2016) Inhibition of Mammary Cancer Progression in Fetal Alcohol Exposed Rats by ?-Endorphin Neurons. Alcohol Clin Exp Res 40:134-40|
|Logan, Ryan W; Wynne, Olivia; Maglakelidze, George et al. (2015) ?-Endorphin neuronal transplantation into the hypothalamus alters anxiety-like behaviors in prenatal alcohol-exposed rats and alcohol-non-preferring and alcohol-preferring rats. Alcohol Clin Exp Res 39:146-57|
|Zhang, Changqing; Murugan, Sengottuvelan; Boyadjieva, Nadka et al. (2015) Beta-endorphin cell therapy for cancer prevention. Cancer Prev Res (Phila) 8:56-67|
|Sarkar, Dipak K (2015) Fetal alcohol exposure increases susceptibility to carcinogenesis and promotes tumor progression in prostate gland. Adv Exp Med Biol 815:389-402|
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