Genetic Approaches to Hypothalamic-Pituitary-Adrenal Axis Regulation

The normal function of the hypothalamic-pituitary-adrenal (HPA) axis, and resultant glucocorticoid (GC) secretion, is essential for human health. Disruption of GC regulation is associated with pathologic, psychological, and physiological disease states such as depression, post-traumatic stress disorder, hypertension, diabetes, and osteopenia, among others. As such, understanding the mechanisms by which HPA output is tightly regulated in its responses to environmental stressors and circadian cues has been an active area of investigation for decades. Over the last 20 years, however, advances in gene targeting and genome modification in rodent models have allowed the detailed dissection of roles for key molecular mediators and brain regions responsible for this control in vivo to emerge. Here, we summarize work done to elucidate the function of critical neuropeptide systems, GC-signaling targets, and inflammation-associated pathways in HPA axis regulation and behavior, and highlight areas for future investigation.     

Intracardiac transplantation of a mixed population of bone marrow cells improves both regional systolic contractility and diastolic relaxation.

BACKGROUND: Pre-clinical and clinical studies suggest that transplantation of bone marrow-derived stem cells can improve global cardiac function. However, no quantitative assessment of regional systolic contraction and correlation with phenotype has been made. Therefore, we used our model of cryoinfarcted rabbit myocardium for intracardiac transplantation of a mixed population of bone marrow-derived cells and assessed both regional function and myogenic conversion of the cells. METHODS: Nineteen New Zealand white rabbits underwent cryoinjury of the left ventricle. Autologous bone marrow (BM) cells were expanded in vitro. After 2 weeks, either 1 x 10(8) mixed BM-derived progenitor cells (BM group, n = 11) or vehicle (control group, n = 8) were injected into the cryoinjured region. Regional systolic function was measured using micromanometry and sonomicrometry before and 4 weeks after cell injection; cell phenotype was evaluated histologically. RESULTS: All animals in the BM group significantly improved both systolic shortening (0.11 +/- 0.7 vs -0.05 +/- 0.05 mm in the control group, p < 0.05) and regional stroke work when compared with control (9.6 +/- 2.4 vs -1.2 +/- 1.2 mm . mm Hg, p < 0.003). In addition, the BM group had improved global diastolic function, as measured by minimum dP/dt and end-diastolic pressure. On histologic assessment, BM cells differentiated toward a myogenic phenotype. CONCLUSIONS: Transplanting a mixed population of marrow-derived cells that can adopt a myogenic phenotype improves regional contractility and diastolic relaxation after myocardial infarction.     

Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy

Human Molecular     

Relationship among the fatty acid composition of various lipid fractions in normally nourished German adults.

The relationship among the fatty acid (FA) composition of plasma cholesteryl esters (CE), plasma phospholipids (PL), total erythrocyte lipids, erythrocyte phosphatidylethanolamine (PE), erythrocyte phosphatidylcholine (PC), and total lipids of the subcutaneous fat (SCF) was investigated by parallel analyses of samples from 47 normally nourished German adults. Each lipid fraction revealed a characteristic FA pattern. A close relation between major FA in plasma lipids, especially in CE, and those in PC was found. The FA composition of PE, however, appeared to be more independent from plasma values. Of all FA in SCF only linoleic acid values showed a correlation to the values in CE and PC. It is concluded that, in clinical studies, FA analyses of total plasma lipids or total erythrocyte lipids fractions should be avoided in favour of separate analyses of various lipid fractions.     

Human X-chromosomal lineages in Europe reveal Middle Eastern and Asiatic contacts

Within Europe, classical genetic markers, nuclear autosomal and Y-chromosome DNA polymorphisms display an east-west frequency gradient. This has been taken as evidence for the westward migration of Neolithic farmers from the Middle East. In contrast, most studies of mtDNA variation in Europe and the Middle East have not revealed clinal distributions. Here we report an analysis of dys44 haplotypes, consisting of 35 polymorphisms on an 8 kb segment of the dystrophin gene on Xp21, in a sample of 1203 Eurasian chromosomes. Our results do not show a significant genetic structure in Europe, though when Middle Eastern samples are included a very low but significant genetic structure, rooted in Middle Eastern heterogeneity, is observed. This structure was not correlated to either geography or language, indicating that neither of these factors are a barrier to gene flow within Europe and/or the Middle East. Spatial autocorrelation analysis did not show clinal variation from the Middle East to Europe, though an underlying and ancient east-west cline across the Eurasian continent was detected. Clines provide a strong signal of ancient major population migration(s), and we suggest that the observed cline likely resulted from an ancient, bifurcating migration out of Africa that influenced the colonizing of Europe, Asia and the Americas. Our study reveals that, in addition to settlements from the Near East, Europe has been influenced by other major population movements, such as expansion(s) from Asia, as well as by recent gene flow from within Europe and the Middle East.     

The matrix metalloproteinase-3 (MMP-3) 5A/6A promoter polymorphism is not associated with ischaemic heart disease: analysis employing a family based approach

Matrix metalloproteinase-3 (MMP-3) has been proposed as an important mediator of the atherosclerotic process. The possible role of the functional -1612 5A/6A polymorphism of the MMP-3 gene in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family based tests of association. One thousand and twelve individuals from 386 families with at least one member prematurely affected with IHD were genotyped. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test (PDT), no association between the MMP-3 -1612 5A/6A polymorphism and IHD was found. Our data demonstrate that, in an Irish population, the MMP-3 -1612 5A/6A polymorphism is not associated with IHD.