Biomedical subjects

Karen Coschigano

Publications and source records attributed to Karen Coschigano.

3 recordsLinked to original sources

PubMed2005

Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis.

UNLABELLED: The role of estrogens in the regulation of pubertal growth independently of GH and its receptor was studied in male mice with disrupted GHRKO. E(2) rescued skeletal growth rates in GHRKO associated with an increase in hepatic and serum IGF-I. These data show that E(2) rescues pubertal growth during GH resistance through a novel mechanism of GHR-independent stimulation of hepatic IGF-I production. INTRODUCTION: Growth hormone (GH) and estrogen play a pivotal role in pubertal growth and bone mineral acquisition. Estrogens can affect GH secretion and thereby provide a GH-dependent mechanism for their effects on skeletal growth. It is presently unclear if or to what extent estrogens are able to regulate pubertal growth and bone mineral accrual independently of GH and its receptor. MATERIALS AND METHODS: Estradiol (E(2); 0.03 mug/day by subcutaneous silastic implants) was administered to orchidectomized (ORX) male mice with disrupted GHR (GHRKO) and corresponding WTs during late puberty (6-10 weeks). Longitudinal and radial bone growth, IGF-I in serum and its expression in liver, muscle, and bone, and liver gene expression were studied by histomorphometry, RIA, RT-PCR, microarrays, and Western blotting, respectively. RESULTS: E(2) stimulated not only longitudinal (femur length and growth plate thickness) and radial growth (cortical thickness and periosteal perimeter), but also rescued longitudinal and periosteal growth rates in ORX GHRKO, whereas no significant changes occurred in WT. E(2) thereby upregulated serum IGF-I and liver IGF-I synthesis (+21% and +52%, respectively) in ORX GHRKO, whereas IGF-I synthesis in femur or muscle was unaffected. Study of the underlying mechanism of the stimulation of hepatic IGF-I expression showed that E(2) restored downregulated receptor signaling systems, such as the estrogen receptor alpha and the prolactin receptor. E(2) thereby recovered the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway as evidenced by a significantly increased activation of the transcription factor STAT5 in ORX GHRKO. CONCLUSIONS: Our data show a stimulation of skeletal growth through upregulation of hepatic IGF-I by a hormone other than GH. E(2) rescues pubertal skeletal growth during GH resistance through a novel mechanism of GHR-independent stimulation of IGF-I synthesis in the liver.

Animals↗

PubMed2005

Phenotypical enrichment strategies for microarray data analysis applied in a type II diabetes study.

Combining results from gene microarrays, clinical chemistry, and quantitative tissue histomorphology in an integrated bioinformatics setting enables prioritization of gene families as well as individual genes in a type II diabetes animal study. This new methodology takes advantage of a time-controlled mouse study as the animals progress from a normal phenotype to that of type II diabetes. Profiles from different levels of the biological hierarchy of unpooled entities provide an encompassing, system-wide view of biological changes. Here, phenotypic changes on the tissue-structural and physiological level are used as statistical covariants to enrich the gene expression analysis, suggesting correlative processes between gene expression and phenotype unlocked by multi-sample comparisons. We apply correlative and gene set enrichment procedures and compare the results to differential analysis to identify molecular markers. Evaluation based on ontological classifications proves changes in prioritization of disease-related genes that would have been overlooked by conventional gene expression analyses strategies.

Animals↗

PubMed2002

Impact of growth hormone resistance on female reproductive function: new insights from growth hormone receptor knockout mice.

We examined multiple aspects of reproductive function in growth hormone receptor gene knockout (GHR-KO) and normal mice to clarify the role of growth hormone in female reproduction. In adult animals, estrous cycle duration was comparable in all mice housed individually but was significantly longer in group-housed GHR-KO females. Histological evaluation of ovaries of adult females at estrus showed that the numbers of preovulatory follicles and corpora lutea were significantly reduced in GHR-KO mice, as was the plasma estradiol level. The number of atretic preovulatory follicles was reduced in GHR gene-ablated animals. Although reverse transcription polymerase chain reaction analysis revealed reduced ovarian insulin-like growth factor I (IGF-I) mRNA expression in GHR-KO females, the expression of several steroidogenic enzyme mRNAs did not differ between groups. The numbers of active corpora lutea and uterine implantation sites were reduced in GHR-KO females at Day 7 of gestation. When young females were mated to normal males, latency to first mating and age of the female at first mating were significantly delayed in GHR-KO females, but maternal age at first conception was similar between groups. Significantly fewer virgin GHR-KO females exhibited pseudopregnancies when initially placed with vasectomized normal males than did normal female counterparts. Growth hormone resistance and IGF-I insufficiency negatively impacted 1) follicular development/ovulation rate, 2) sexual maturation, 3) production of and responsiveness to pheromonal signals, and 4) the ability of virgin females to respond to coitus by activation of luteal function. Although GHR-KO female mice are fertile, they exhibit quantitative deficits in various parameters of reproductive function.

Aging↗