Dataset Information

GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes

ABSTRACT: Growth hormone (GH) receptor (GHR) mutations give rise to GH-resistance (Laron syndrome). We previously treated GH-resistant Ghr-/- mice (Laron mice) with adeno-associated virus (AAV) delivering mouse (m)Ghr controlled by a constitutively active liver-specific promoter (HLP). A single injection of AAV-HLP-mGHR resulted in a significant but limited increase in body length and weight, consistent with studies of IGF-1 treatment in humans and mice. Here, we performed RNA-seq on male and female mouse livers comprising the following groups: GHR+/+ (wild-type), GHR-/- (Laron), AAV-HLP-mGHR-treated GHR-/- (treatment group), and AAV-HLP-Luc (Luciferase)-treated GHR-/- (control group). Only four genes showed significant differential expression in GHR -/- mouse liver following Luciferase vector treatment, indicating minimal effect of the AAV-HLP vector. AAV-HLP-mGHR stimulated significant expression changes in 448 genes compared to AAV-HLP-Luc control, substantially fewer than the 2781 genes whose expression was altered in GHR-/- compared to GHR+/+. AAV-HLP-mGHR treatment induced the GH-responsive IGF signaling genes Igf1 and Igfals ~16-fold compared to AAV-HLP-Luc control, but only to 40–45% of GHR+/+ liver levels. The treatment also upregulated a small subset of genes beyond GHR+/+ expression levels (p-adj < 0.05), including the proto-oncogenes Ascl1, Tmprss4, and others. Finally, genes dysregulated upon GHR loss and upregulated in livers of AAV-HLP-mGHR-treated mice were significantly enriched for sex-biased genes, consistent with the major role of GH and GHR in regulating liver sex differences. While gene replacement therapy is a potential therapy for Laron syndrome, an unregulated constitutively active promoter may drive unexpected and unbalanced changes in liver gene expression that will require monitoring.

ORGANISM(S): Mus musculus

PROVIDER: GSE289769 | GEO | 2026/06/18

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:The incidence of pre-diabetes (PD) and Type-2 Diabetes Mellitus (T2D) is a worldwide epidemic. African American (AA) individuals are disproportionately more likely to become diabetic than other ethnic groups. Over the long-term, metabolic complications related to diabetes result in significant alterations in growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Considering the limited exercise-related studies in the area of gene expression changes with disease progression, the objective of this study was to examine differences in exercise-induced gene expression related to the GH and IGF-1 pathways in peripheral blood mononuclear cells (PBMCs) of healthy (CON) and PD AA individuals. Design: Ten subjects [5 PD (age=35±9.3 yr, BMI=32.1±4.0, FBG=101.8±1.3 mg/dl) and 5 CON (age=31±9.4 yr, BMI=29.4±5.2, FBG=82.8±9.7 mg/dl)] had blood drawn for RNA isolation prior to exercise (Pre), immediately following acute moderate intensity exercise on a treadmill (Post-1), 6-hours post (Post-6), and 24-hours post (Post-24). Isolation of mRNA from PBMCs was performed using ficoll separation, while the profiling of mRNA expression was performed using beadchip arrays that were scanned and analyzed by a gene expression module. Scan results were statistically analyzed for a specific list of genes related to GH and IGF-1. GH and IGF-1 protein levels were also assessed in each sample. To address issues of normality, all GH and IGF-1 data were log-transformed prior to analysis. Statistical significance was set at p<0.05. Results: Group differences for GH2 variant 2 (p=0.070) and GH2 variant 3 (p=0.059) were coupled with significant alterations in IGF-1 mRNA over time (p=0.024). A significant interaction between group and time was observed for GHRH mRNA (p=0.008). No group differences were observed in GH AUC (p=0.649), ∆GH (p=0.331), GHrec (p=0.294), or IGF-1 AUC (p=0.865), representing a similar exercise-induced GH and IGF-1 response for both groups. Conclusions: Analysis of GH and IGF-1 related-gene expression indicates that mild elevations in fasting blood glucose and exercise-induced alterations in gene expression are impacted by the prediabetic state.

Dataset Information

GH-resistant (Laron) mice: gene therapy with a liver-specific GH receptor causes unbalanced upregulation of female-biased and growth-related genes

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets