Project description:As part of genetic studies of heart failure in mice, we observed that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observed that expression of genes encoding mitochondrial proteins were higher in males than females in human cohorts. Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesized that mitochondrial sex differences might underlie this bias. We tested this in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we found that mitochondrial gene expression was highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirmed that mitochondrial function differed between sexes and was strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identified the mitochondrial protein Acsl6 as a genetic determinant of diastolic function. We validated its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.
Project description:Somatic cell nuclear transfer (SCNT) and induced pluripotent stem cells (iPSCs) represent two major approaches for somatic cell reprogramming. However, little attention has been paid to the ability of these two strategies in rejuvenating cells from donors with aging associated syndrome. Here, we utilized telomerase deficient (Terc-/-) mice to probe this question. SCNT-derived embryonic stem cells (ntESCs) and iPSCs were successfully derived from second generation (G2) and third generation (G3) of Terc-/- mice, and ntESCs showed better differentiation potential and self-renewal ability. Telomeres lengthened extensively in cloned embryos while remained or slightly increased in the process of iPSCs induction. Furthermore, G3 ntESCs exhibited improvement of telomere capping function as evidenced by decreased signal free ends and chromosome end-to-end fusion events. In contrast, there was a further decline of telomere capping function in G3 iPSCs. In addition to telomere dysfunction, mitochondria function was severely impaired in G3 iPSCs as evidenced by oxygen consumption rate (OCR) decline, reactive oxygen species (ROS) accumulation and dramatically increased mitochondria genome mutations while these deficiencies were greatly mitigated in G3 ntESCs. Our data proved the principle that SCNT-mediated reprogramming appears more superior than transcription factors induced reprogramming in terms of the resetting of telomere quality and mitochondria function, and thus, providing valuable information for further improvement of transcription factors mediated reprogramming. We compared the gene expression profile of G3 Terc-/- ntES and G3 Terc-/- iPS. Three biological repeats were included for each cell line.
Project description:In the field, adult male rodents are more frequently infected with hantaviruses than females. Early data suggests that sex steroid hormones modulate sex differences in host immune response. This project focuses on elucidating sex differences in gene expression in the lungs of infected males 15 and 40 days post infection with Seoul virus (naturally occurring hantavirus in Norway rats) relative to infected females 15 and 40 days post infection on 12 RG_U34 GeneChips. Keywords: other
Project description:Somatic cell nuclear transfer (SCNT) and induced pluripotent stem cells (iPSCs) represent two major approaches for somatic cell reprogramming. However, little attention has been paid to the ability of these two strategies in rejuvenating cells from donors with aging associated syndrome. Here, we utilized telomerase deficient (Terc-/-) mice to probe this question. SCNT-derived embryonic stem cells (ntESCs) and iPSCs were successfully derived from second generation (G2) and third generation (G3) of Terc-/- mice, and ntESCs showed better differentiation potential and self-renewal ability. Telomeres lengthened extensively in cloned embryos while remained or slightly increased in the process of iPSCs induction. Furthermore, G3 ntESCs exhibited improvement of telomere capping function as evidenced by decreased signal free ends and chromosome end-to-end fusion events. In contrast, there was a further decline of telomere capping function in G3 iPSCs. In addition to telomere dysfunction, mitochondria function was severely impaired in G3 iPSCs as evidenced by oxygen consumption rate (OCR) decline, reactive oxygen species (ROS) accumulation and dramatically increased mitochondria genome mutations while these deficiencies were greatly mitigated in G3 ntESCs. Our data proved the principle that SCNT-mediated reprogramming appears more superior than transcription factors induced reprogramming in terms of the resetting of telomere quality and mitochondria function, and thus, providing valuable information for further improvement of transcription factors mediated reprogramming.
Project description:Heart failure and other cardiomyopathies have distinct presentations in males versus females that are often overlooked, leading to ineffective treatment, and contributing to the growing mortality from heart diseases. Understanding the differences in the pathogenesis of heart disease in males and females can guide early diagnostics and sex-specific therapy. Thus, there is a pressing need to investigate the sex-specificity of promoter and enhancer activity in the pathogenesis of heart failure. Here, using cap analysis of gene expression we characterize the sex-specific activity of transcriptional regulatory elements in 17 male and 14 female healthy and failing hearts. We show that differentially expressed transcribed regulatory elements between two sexes are spread throughout the entire genome in healthy and failing atria and ventricles, and are related to immune system, metabolic, cardiomyocyte function, and developmental pathways. Moreover, we found 720 genes with sex-dependent promoter switching of which 40 switched dominant promoters. Among those was CREM, a transcription factor, with a short repressive dominant isoform exclusive for males. CREM is related to extensive β-adrenergic receptor stimulation that leads to elevated arrhythmic activity, hypertrophy and heart dysfunction. Furthermore, we identified metabolic pathways being more responsible for female aging and developmental pathways for male aging. We also showed sex-specific aging patterns, such as age-specific promoter usage of 1,100 genes that behaved differently depending on sex, including UCKL1 and HAND2 linked to uridine metabolism and cardiac development, respectively.
Project description:Heart failure represents a leading cause of mortality in the elderly population. Although aging features include diastolic dysfunction and interstitial fibrosis in both males and females, it becomes increasingly apparent that aged male and female hearts are phenotypically different. There were fundamental differences in extracellular matrix (ECM) composition and architecture and heart function indices at the baseline, which were further accentuated by Aicar treatment. By combining in vivo, ex vivo, and in vitro strategies, we demonstrated that there are sex-specific features that influence the response to pharmacological intervention in the aging mouse heart.
Project description:To investigate the relationship between the resistance of male and female Penaeus vannamei and their immunity, we collected hemocytes from shrimps stimulated by Vibrio parahaemolyticus.
Project description:In this study, we investigated potential sex differences in a Rbm20 knockout mouse model. We used RNA sequencing of bulk RNA from the left ventricle of male and female wildtype and Rbm20 knockout mice.