Biology subjects

Karumanchi, S. A.

Publications and source records attributed to Karumanchi, S. A..

6 recordsLinked to original sources

bioRxiv2025

The Role of Supraoptic Hypothalamic Arginine Vasopressin Neurons in Aging-Associated Water Balance and Thermoregulatory Deficits

Aging disrupts physiological homeostasis, impairing thermoregulation, metabolism, and water balance, but the underlying neural mechanisms remain unclear. Here, we identify arginine vasopressin (AVP) neurons in the supraoptic nucleus (SON) of the hypothalamus as a critical driver of these changes. Using single-nucleus RNA-sequencing of the anterior hypothalamus in young and aged mice, we found Avp to be one of the most upregulated neuronal transcripts with age. Aged SONAVP neurons displayed enlarged size and heightened excitability, features consistent with hyperactivity. Functionally, chemogenetic activation of SONAVP neurons in young mice reproduced aging-associated phenotypes including hypothermia, reduced energy expenditure, and suppressed water intake. Conversely, knockdown of Avp in the SON of aged mice restored water balance, partially improved thermoregulation and systemic metabolism. Pharmacological inhibition of AVP receptors revealed that neuroendocrine release of AVP drives homeostatic deficits, with distinct roles for V1A and V2 receptors. Senolytic drug treatment improved systemic metabolism and reduced inflammaging but does not rescue hypothalamic AVP dysfunction, underscoring a brain autonomous mechanism of age-related physiological failure. Together, our findings establish SONAVP neuronal hyperactivity as a driver of impaired homeostasis with age and suggest that targeted modulation of neuroendocrine AVP signaling may offer a therapeutic strategy to alleviate age-associated water balance defects.

physiology↗

bioRxiv2024

Butyrophilin 2A2 promotes T cell immunoregulation by enhancing CD45 phosphatase activity within the immune synapse

B7 costimulatory family member Butyrophilin 2A2 (BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increased murine CD4+Foxp3+ regulatory T cells (Treg) and reduced T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 treatment reduced clinical expression of two murine autoimmune disease models and increased Treg/Th17 ratios. Analyses of BTN2A2-deficient animals showed exacerbated disease associated with reduced Treg/Th17 ratios. Addition of BTN2A2 to human mixed lymphocyte responses similarly enhanced human Treg and suppressed Th17 cells and was CD45 phosphatase dependent. Together, our studies identify BTN2A2 as a physiological CD45RO ligand that enhances CD45 phosphatase activity in murine and human T cells, providing mechanisms for BTN2A2-mediated amelioration of autoimmunity. SummaryButyrophilin 2A2 ameliorates autoimmunity by binding to CD45RO on activated T cell surfaces leading to dampened TCR signaling which in turn leads to expansion of T regulatory cells and reduction of Th17 differentiation.

immunology↗

bioRxiv2023

High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester

BackgroundThe placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal- fetal health. MethodsThe normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background. ResultsPlacenta expresses 14,979 mRNAs above sequencing noise (TPM>0.66), with 1,545 stably expressed genes across gestation. Differentially expressed genes account for 86.7% of genes in the full cohort (FDR<0.05). Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR<0.001, fold change>1.5), there are 6,941 differentially expressed protein coding genes (3,206 upregulated in first and 3,735 upregulated in third trimester). ConclusionThis is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and stably expressed genes may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers in maternal-fetal disease.

developmental biology↗

bioRxiv2022

Hypoxia-inducible factor 1 signaling drives placental aging and can elicit inflammatory changes in uterine myocytes

Most cases of preterm labor have unknown cause, and the burden of preterm birth is immense. Placental aging has been proposed to promote labor onset, but specific mechanisms remain elusive. We report findings stemming from unbiased transcriptomic analysis of mouse placenta, which revealed that hypoxia-inducible factor 1 (HIF-1) stabilization is a hallmark of advanced gestational timepoints, accompanied by mitochondrial dysregulation and cellular senescence; we detected similar effects in aging human placenta. In parallel in primary mouse trophoblasts and human choriocarcinoma cells, we modeled HIF-1 induction and demonstrated resultant mitochondrial dysfunction and cellular senescence. Transcriptomic analysis revealed that HIF-1 stabilization recapitulated gene signatures observed in aged placenta. Further, conditioned media from trophoblasts following HIF-1 induction promoted contractility in immortalized uterine myocytes, suggesting a mechanism by which the aging placenta may drive the transition from uterine quiescence to contractility at the onset of labor. Finally, pharmacological induction of HIF-1 via intraperitoneal administration of dimethyloxalyl glycine (DMOG) to pregnant mice caused preterm labor. These results provide clear evidence for placental aging in normal pregnancy, and demonstrate how HIF-1 signaling in late gestation may be a causal determinant of the mitochondrial dysfunction and senescence observed within the trophoblast as well as a trigger for uterine contraction.

physiology↗

bioRxiv2020

Risk of preeclampsia in patients with genetic predisposition to common medical conditions: a case-control study

ObjectiveTo assess whether women with a genetic predisposition to medical conditions known to increase preeclampsia risk have an increased risk of preeclampsia in pregnancy. DesignCase-control study. Setting and populationPreeclampsia cases (n=498) and controls (n=1864) of European ancestry from 5 US sites genotyped on a cardiovascular gene-centric array. MethodsSignificant single nucleotide polymorphisms (SNPs) from 21 traits in 7 disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal, thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous, scaled genetic instrument with preeclampsia. Odds of preeclampsia were compared across quartiles of the genetic instrument and evaluated for significance using a test for trend. Main Outcome Measurespreeclampsia. ResultsAn increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of preeclampsia (DBP: overall OR 1.11 (1.01-1.21), p=0.025; BMI: OR 1.10 (1.00-1.20), p=0.042), while risk alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89 (0.82-0.97), p=0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset (<34 weeks) preeclampsia cases (OR 1.30 (1.08-1.56), p=0.005). For all other traits, the genetic instrument was not robustly associated with preeclampsia risk. ConclusionsThese results suggest that the underlying genetic architecture of preeclampsia is shared with other disorders, specifically hypertension and obesity. TWEETABLE ABSTRACTGenetic predisposition to increased diastolic blood pressure and obesity increases the risk of preeclampsia.

genetics↗

bioRxiv2019

The maternal-fetal interface of successful pregnancies and impact of fetal sex using single cell sequencing

The first trimester is a critical window of maternal-fetal communication for pregnancy. Therefore, we characterized crosstalk in ongoing human pregnancies at 11-13 weeks gestation. RNA-sequencing of matched maternal decidua and placenta identified 818 receptors and 3502 ligands, including 126 differentially expressed receptor-ligand pairs. Using single cell RNA-sequencing to further dissect placenta heterogeneity, we identified five major cell types (trophoblasts, stromal cells, hofbauer cells, antigen presenting cells and endothelial cells) with unique crosstalk at the maternal-fetal interface. We identified seven unique trophoblast subclusters, including new subtypes that transition into the terminal cell types, extra-villous trophoblasts and syncytiotrophoblasts. As fetal sex impacts pregnancy, we analyzed sex differences in each cell type and identified differences in immune cell function. TGF{beta}1, {beta}-estradiol, and dihydrotestosterone emerge as upstream regulators of sexually dimorphic genes in a cell type specific manner. Thus, the fetal contribution at the maternal-fetal interface is cell and sex specific.

developmental biology↗