Project 1: Ligand-independent ERbeta signaling in the aged brain (NIH AG033605).
Estrogen receptors (ER) are classified as ligand-activated transcription factors. For many years, the prevailing theory held that these multifaceted members of the nuclear receptor family were quiescent in the absence of ligand binding. Over a decade ago, we showed that apo-ERbeta was actively engaged in both transcriptional repression and transcriptional activation depending on the specific cis-acting sequence of the gene promoter. Since then, we have uncovered 3 key molecular factors that direct ligand-independent function of ERbeta in the aged brain:receptor phosphorylation, alternative RNA splicing, and coregulatory protein interactions. We propose that these three processes are inter-linked and each contribute to the overall ERbeta signaling signature in diverse tissues. Our immediate goal is to gain a deeper understanding of the contributions of these factors in directing ERbeta ligand-independent signaling in the aged brain, with the long-term goal of attaining a molecular rationale for assessing cost/benefit decisions of hormone replacement therapy in postmenopausal women
Project 2: Regulation of miRNAs in the brain (NIH AG082135)
Nearly 2,000 microRNAs (miRNA) have been identified in humans to date and it has been predicted that they regulate up to 60% of all protein expression in mammalian cells, underscoring their fundamental importance in all basic physiological processes. Despite their critical role, little is known about the tissue-specific regulation of miRNA biosynthesis and processing. In general, global miRNA biogenesis follows a well-defined pathway beginning with the generation of a long primary transcript (pri-miR) and ending with a single-stranded 22 nt mature miRNA product. There are several steps along this pathway that are potential points where unique tissue- and age-specific expression of individual miRNAs could occur. Our research has shown that estrogen, age, and alcohol all regulate specific subsets of miRNAs in and brain region–specific pattern. Circulating estrogens dynamically fluctuate across the lifespan; they rapidly rise at puberty, peak during the reproductively competent years, and then sharply decline at menopause. Thus, estrogen regulation of miRNAs must be temporally specific to ensure appropriate production of select mature miRNAs at the correct life stages. Moreover, binge alcohol consumption can disrupt normal miRNA expression patterns during this critical period of adolescent brain maturation. Our long-term goal for this project is to gain a better understanding of how these factors impact canonical miRNA biogenesis pathways and also understand how miRNA stability is altered in aging and Alzheimer Disease.
Project 3: Sex differences in Alzheimer Disease (Alzheimer Association Research Grant 924957)
The incidence of Alzheimer’s Disease (AD) is higher in women than men, with women accounting for approximately 2/3 of all diagnosed patients (Alzheimer Foundation annual report, 2021). The basis for this sex bias could be a reflection of women living longer than men, but whether there are biological factors that contribute to this sex bias remains controversial. Evidence for at least a partial contribution of biological sex differences is demonstrated by the fact that women have higher diagnosed rates than men at all ages, AD-related cognitive impairment progresses at a faster rate in women, and AD progression has been linked to early onset menopause. The sex bias in AD incidence has historically focused on hormonal factors, yet the literature clearly shows that hormones are not a driving force or a useful therapeutic tool. Estrogen therapy decreases the risk of AD when administered close to menopause, but is detrimental in later years. We propose there is an age-related switch in estrogen receptor (ER) signaling that predisposes women to AD. ERbeta is a transcription factor that represses genes with AP-1 (activator protein-1) motifs in their promoters, several of which have been implicated in AD progression and severity. This project aims to determine how ERbeta signaling shifts to AP-1-mediated genes in AD.
Project 4: Long-term neurobiological consequences of adolescent binge alcohol exposure (NIH AA021517)
Several decades of research have proven that maternal alcohol consumption during critical periods of fetal brain development leads to devastating long-term consequences on cognitive function and social behavior. However, less is known about the long-term consequences of alcohol consumption during puberty, which is an equally dynamic and critical period of brain development. During puberty extensive remodeling of the brain occurs that includes changes in cortical gray matter, synaptic connectivity, and increased neurogenesis. Patterns of alcohol use during this developmental period can lead to permanent changes in brain function that often manifest in adulthood as psychological disorders, such as depression and anxiety. Moreover, correlative studies have demonstrated that over 50% of patients with alcohol dependency also have anxiety- or depression-related behavioral disorders, and these types of disorders are often associated with an abnormal stress response. We have demonstrated that repeated binge-pattern EtOH exposure during pubertal development caused substantial dysregulation of the adolescent and adult rat neuroendocrine stress response. The molecular basis for this dysregulation appears to be, in part, altered glucocorticoid receptor (GR) signaling, which leads to a hyper-vigilance behavioral phenotype in adulthood. In addition, epigenetic alterations are present in the adult brain, through altered microRNA expression. We have also determined many of these phenotypic changes are transmitted to the next generation, including widespread gene expression changes, and altered somatic development, along with altered hypothalamic development in offspring. These effects are transmitted via epigenetic mutations to the DNA methylation patterns long after the binge-pattern alcohol exposure has ceased.