1,721,008 research outputs found
Take Your Telomeres To Church: The Association between Religiosity and Telomere Length in the Fragile Families and Child Wellbeing Study
No full textAlthough religiosity has been associated with an array of positive health outcomes, little is known about the biological mechanisms underlying this relationship. Stress is a potential mechanism: religiosity may work through various social and biological mechanisms to buffer against the deleterious allostatic load stress exerts on the body. To determine the cumulative effect of religion on health, this study investigated the association between mothers’ early religious behavior, their telomere length and their children’s telomere length in the Fragile Families and Child Wellbeing study, a sample of nearly 5000 families from large cities across the US. Because stress has been identified as a major determinant of telomere erosion throughout one's life, telomere length is a biomarker that allows for a quantitative analysis of the effect of stress and religiosity on health. The study also examined how socioeconomic status, mental health, social support and individual genetic sensitivity moderate this relationship, and found that religious attendance was significantly associated with longer TL among mothers and children, and was more strongly associated with longer TL in children from families of a higher socioeconomic status. In addition, intrinsic religiosity was more strongly associated with longer TL among mothers at higher levels of instrumental support. Overall, religiosity was associated with longer TL, and this relation was stronger in environments with lower stress. Religion is therefore a valuable and easily accessible resource for enhancing the health of disadvantaged populations
Fly-ing Under the Radar: Sexual Dimorphism in Responses to Repetitive Traumatic Brain Injury in Drosophila
No full textTraumatic Brain Injury (TBI) is a leading cause of death for individuals younger than forty and is the greatest environmental risk factor for the accelerated development of neurodegenerative diseases. As female participation in sports and enrollment in the military increases, there has been an elevation of TBI rates among females. Growing evidence suggests sex differences in clinical presentation, morbidity, and mortality following TBI. Despite the health consequences of TBI and the mounting evidence of a sexually dimorphic response, females remain underrepresented in TBI pre-clinical research, and medical interventions remain unspecific to sex. Studies have shown that Drosophila is an excellent model of TBI and TBI-induced neurodegeneration. Drosophila shares several hallmarks of neurotrauma with humans, including dose-dependent motor, neurological, and memory deficits as well as phased immune activation, disorganized glial response, and acute activation of cellular stress response. Their short reproductive cycles also make them an ideal model for studying long-term TBI-associated neurodegeneration. This study utilized a strike device with a gas-propelled impactor to conduct controlled, head-specific injuries in a Drosophila model of repetitive TBI (rTBI) characterized by Katchur et al. (Katchur, unpublished) I first characterize Drosophila behavior following rTBI by evaluating survival and locomotion. Males had a significant decrease in lifespan at 1d post-injury, while females did not. Both sexes had significant deficits in locomotion at 1d post-injury, but males recovered locomotion by 7d post-injury, while females remained hypoactive at 14d post-injury. In addition, preliminary proteomic analysis of fly brains showed sex differences in proteomic shifts in several pathways following injury, particularly in immune and mitochondrial genes. Together, my results present preliminary evidence that there is sexual dimorphism in both behavior and proteomic regulation following rTBI
Stress Alters Telomere Length and Telomeric Gene Expression
No full textTelomere shortening is an inherent feature of the DNA replication
mechanism. Although robust evidence exists for the acceleration of this process
under conditions of chronic stress, the molecular and biochemical underpinnings
of this process are poorly understood. Here we employ Schizosaccharomyces
pombe to establish a model for the effects of chronic environmental stressors on
telomere length. We show that environmental stresses alter the growth kinetics of
fission yeast and disrupt telomere length homeostasis. Most strikingly, heat and
caffeine stress shortened telomeres and ethanol stress elongated telomeres. To
investigate changes in gene expression associated with chronic external stresses,
we performed total transcriptome sequencing on RNA extracted from cells
exposed to these three stress conditions. The RNA-seq data revealed that stress
dramatically altered the gene expression profile compared to cells grown under
wild-type conditions. Although preliminary data suggests stress changes the
expression of telomeric genes, this data is currently being validated by more
sensitive quantitative methods. Additionally, we have extended our model in S.
pombe to a mammalian system by exposing human foreskin fibroblasts to
biological compounds associated with stress in humans and assaying concomitant
changes in telomerase activity. We find that treatment with cortisol reduces
telomerase activity in this cell line. These findings contribute to the understanding
of how chronic stress alters telomere length and gene expression
Steroid Hormones Alter Telomerase Activity in 293T Cells
No full textTelomeres are nucleoprotein complexes that cap the ends of each strand of DNA in order to prevent the loss of genetic information during replication, protect the DNA from degradation, and inhibit chromosome fusion. During replication in most cells, telomeres shorten because of the end replication problem and continue to do so until they reach a critical length, resulting in cellular senescence. Telomere shortening is a natural process; however, individuals exposed to chronic stress have been observed to have shorter telomeres then those who have not. The biological significance and mechanism of stress-related telomere attrition are unclear. The aim of this work is to establish a model of stress-based alterations in telomerase (the ribonucleoprotein complex that replenishestelomeres) activity in 293T cells. The literature is unclear as to whether telomerase activity in these cells is regulated. Cells were exposed to physiological and supraphysiological levels of cortisol, estrogen, and testosterone. Utilizing FACS, the percent of cells in each phase of the cell cycle were quantified after stressing to correct telomerase activity by the amount of cells in S-phase, as telomeres are replenished in S-phase. Here, telomerase activity in 293T cells is shown to be partially regulated bypositive regulation of estrogen and testosterone. Negative regulation from cortisol appeared to be insignificant. cDNA was then prepared from testosterone trials in both 293T and Hff cells to compare hTERT expression, the catalytic subunit of telomerase. The prelimary qPCR results show conflicting trends in hTERT expression and this assay is ongoing. The positive regulation of 293T cells by stress can provide insights into the molecular basis of stress-induced telomere shortening through further study
DNA Methylation as a Candidate Mechanism Behind Stress-Attributed Telomere Shortening
No full textA network of proteins and enzymes facilitate the regulation of telomeres, but research is still unclear regarding the mechanism that underlies telomere maintenance. In brief, telomerase, an enzyme made up of subunits hTERT and hRT, adds telomeric repeats on the ends of chromosomes. Previous literature have observed significant telomere shortening on the ends of chromosomes in disadvantaged individuals exposed chronic stressors when compared to their advantaged counterparts. Alongside these studies, preliminary results have suggested that genes involved in maintaining telomere length may be regulated by DNA methylation, an epigenetic mechanism. In particular, the gene Mad1L1, a negative regulator of hTERT, was found to be positively correlated with telomere length. Our study aims to unpack plausible mechanisms that are connected to telomere maintenance. In doing so, our objective is to perform a functional assay to understand stress-associated DNA methylation and its effects on telomere biology. To develop a basis for this functional assay, we attempted to construct a necessary positive control, comprising of the prMTM1 promoter region and pCpGL vector backbone. Future directions include the construction of the experimental vector with prMad1L1 region and a Dual-Luciferase Promoter Functional Assay with this experimental construct
Use of an In Vitro Reporter Assay System to Validate the Association Between Promoter Methylation and Telomere Length
No full textTelomeres are repetitive non-coding sequences found at the ends of chromosomes involved in protecting the genome that can serve as a biomarker of a cell’s chronological age. While research on the mechanisms underlying telomere maintenance is still underway, recent studies have demonstrated a direct relationship between telomere length and overall health, and that individuals who experience excessive and chronic stress may have shorter telomeres than unstressed individuals. To better understand the mechanisms involved in telomere length homeostasis, we postulate that epigenetic processes play an important role in regulating telomere length, in particular by altering the activity of telomerase, an enzyme that adds telomeric repeats to the ends of chromosomes. Few studies have examined the relationship between DNA methylation, the addition of a methyl group to a cytosine preceding a guanosine, and telomere length. Thus, the aim of the present study was to elucidate the process by which genes involved in telomere maintenance may be epigenetically modified in response to stressors. Using data from the Fragile Families and Child Wellbeing Study, which provides a longitudinal analysis of methylation profiles and telomere lengths in advantaged and disadvantaged populations, we identified two genes, SOX3 and MAD1L1, whose promoters were differentially methylated in response to stress and significantly correlated with telomere length. By establishing an in vitro functional assay, we tested the effects of DNA methylation on downstream transcription and found that increased methylation attenuated gene expression. Future directions include validating the results of the functional assay to lay the groundwork for further analysis of candidate promoter regions, as well as other gene regulatory elements and forms of epigenetic regulation. In addition, we hope to further unpack the biological effects of stress by treating cells with cortisol, a key player in the stress response, and observing changes in the expression of SOX3, MAD1L1, and telomerase
GERM CELL GENOTOXICITY THE LASTING EFFECTS OF PEDIATRIC CANCER THERAPY
No full textIn this thesis, I set out to examine fertility as a late effect of pediatric
cancer therapy. I determine why fertility is an inadequate measure of the
reproductive fitness of adult cancer survivors and explore the causes of deficits in
fertility after pediatric cancer therapy. I focus mainly on the male germ cell line,
exploring various sperm genomic damages that occur as a result of chemotherapy
and/or radiotherapy in childhood and adolescence. Although sperm chromosome
aneuploidy presents as a consequence of pediatric cancer therapy, I worry more
with sperm DNA fragmentation, which includes single-strand and double-strand
DNA breaks, which are genotoxic and have the ability to be transmitted to
offspring. I find, however, that although DNA-impaired spermatozoa may
fertilize an egg, it is unlikely for these damages to remain in the embryo or for the
embryo to remain
The Impact of an Impact: Telomere Length and Telomerase Activity in Cells of the Central Nervous System Following Moderate Controlled Cortical Impact Injuries in Mice
No full textTraumatic brain injury (TBI) affects over 57 million people globally each year, of
whom 1.4 million live in the United States. There are 475,000 new cases of pediatric
traumatic brain injury per year, accounting for 3,000 to 4,000 deaths. Traumatic
brain injury (TBI) differs from ischemic stroke and other non-mechanical
injuries in that head trauma exposes cells of the central nervous system (CNS) to
shear force, tensile stress, and compression forces. In addition to physical disruption
of neural structures, these forces induce damaging activation of cellular stress
and inflammation pathways. The resulting cellular processes following a traumatic
brain injury may damage DNA, including the telomeres. Telomeres are the end
chromosomal structures comprised of tandem repeating base pairs (of nucleotide
sequence TTAGGG) that protect genetic information. Due to the end replication
problem, in the absence of telomeres, the chromosomal ends shorten as DNA replicates.
The presence of the telomere buffers this effect. In some cell lineages, telomerase
maintains telomere length during replication. In most somatic cells, however,
telomere attrition occurs naturally due to aging, oxidative stress, and other mechanisms.
Further, telomerase activity is implicated in neurogenesis and may affect
how neural and glial cells survive. Cells with active telomerase are more resistant
to cellular apoptosis. Recent literature suggests that telomere attrition may be accelerated
by TBI and TBI may induce telomerase activity. Previous studies show
that telomerase activity was induced in mice hippocampi following kainate-induced
seizures and telomere lengths shortened in some rats as a result of a mild concussive
TBI, but experimental conditions did not permit a definitive statement as to the link between the level of trauma and telomere length. It is not clear how a moderate
traumatic brain injury affects telomerase activity and telomere lengths. To address
this gap, we sought to measure telomerase activity and telomere lengths in cells
of the CNS both 24 hours and 14 days following a moderate Controlled Cortical
Impact (CCI) injury in adult male mice. We found changes in telomerase activity
in the ipsilateral cortex, thalamus, and hippocampus 24 hours following injury,
and telomerase activity remained present in these regions 14 days following injury.
Telomerase activity in some tissues were statistically significant when compared to
controls. Additionally, we found significant telomere length changes in the cells
of the CNS 14 days following TBI. Telomere elongation occurred in the ipsilateral
cortex, telomere maintenance occurred in the ipsilateral hippocampus, and telomere
attrition occurred in the ipsilateral thalamus. Correlation between a moderate
traumatic brain injury and telomere length mediated by telomerase activity 1 day
after a moderate CCI injury may suggest a possible molecular mechanism by which
telomeres change after a traumatic brain injury, providing insight for possible future
medical treatment and intervention. Future studies should investigate the types of
cells expressing telomerase and changes in telomere lengths to better understand
the implications that telomere length and telomerase activity have in neurogenesis
and to elucidate the cellular mechanism by which telomere changes occur following
a traumatic brain injury
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