Many needles in genetic haystack
Genes (and cellular pathways) rarely work in isolation to cause disease; they interact with other genes and pathways. Genome-wide association studies (GWAS) – which investigate genetic variants for association with particular diseases or traits – typically report single gene variants associated with a disease rather than identifying gene or pathway interactions.
Zhongming Zhao, Ph.D., and colleagues are looking for ways to expand the use of GWAS beyond single markers, to detect genes that may work together in mediating complex diseases. They developed a new tool – dubbed dmGWAS – which integrates GWAS signals into the human interactome (the set of all molecular interactions in a cell). They now demonstrate, using breast and pancreatic cancer datasets, that dmGWAS successfully identifies significant genetic modules and candidate genes, including many that remained unidentified in typical single-marker analysis.
This approach, reported in the journal Bioinformatics, offers a powerful new tool for identifying multiple common variants associated with complex diseases. The dmGWAS tool is publicly available at: http://bioinfo.mc.vanderbilt.edu/dmGWAS.html.
— Melissa Marino
Fountain of youth for stem cells?
Bone marrow-derived mesenchymal stem cells (MSCs) have shown promise in regenerating damaged heart tissue and in facilitating wound healing. But regulation of MSC self-renewal – the ability of cells to proliferate and survive, but not differentiate into more mature cell types – is poorly understood, which limits the therapeutic potential of these cells.
Graduate student Maria Alfaro, Pampee Young, M.D., Ph.D., and colleagues previously showed that bumping up expression of a protein called sFRP2 increased proliferation of MSCs. In the Nov. 12 Journal of Biological Chemistry, they report that sFRP2 also prevents MSCs from committing suicide and inhibits these cells from differentiating into more mature bone and cartilage cells by inhibiting Wnt and BMP signaling. In heart and wound tissue treated with MSCs, increasing sFRP2 expression reduced calcification, a reported adverse side effect of MSC therapy.
The study identifies mechanisms by which sFRP2 enhances stem cell self-renewal to promote tissue regeneration – findings that could lead to improved cell therapies for heart and wound repair.
— Melissa Marino
No head rush, please
Orthostatic hypotension – a sudden drop in blood pressure that causes dizziness and near-fainting (a “head rush”) – is the main cause of disability in patients with autonomic failure, a disorder of the nervous system that normally controls functions like heart rate, digestion and respiration.
Cyndya Shibao, Italo Biaggioni, M.D., and colleagues compared the ability of two different drugs (alone and in combination) to improve blood pressure on standing in 31 patients with severe autonomic failure. They report in the November issue of Hypertension that the drug yohimbine – a plant-derived compound with stimulant and aphrodisiac effects – significantly improved standing blood pressure compared to placebo, and that pyridostigmine did not. Yohimbine and pyridostigmine in combination did not improve blood pressure more than yohimbine alone.
Because yohimbine increases blood pressure by activating the sympathetic nervous system, the findings suggest that patients with autonomic failure still have residual sympathetic activity and that this mechanism is an important therapeutic target.
— Leigh MacMillan
Clues to immune system-linked blues
Alterations in the immune system – such as the production of pro-inflammatory cytokines stimulated by viral or bacterial infection – have been associated with psychiatric illness. Randy Blakely, Ph.D., William Hewlett, M.D., Ph.D., and colleagues previously demonstrated in vitro that inflammatory cytokines enhance the activity of the serotonin transporter (SERT), a target of medications for depression and other psychiatric disorders.
In the December issue of Neuropsychopharmacology, the investigators report that systemic immune system activation in mice, by injection of the cytokine-inducer LPS, enhances brain SERT activity. Along with SERT stimulation by LPS, the mice have increased despair-like behavior in two tests that model behavioral despair (depression). The researchers also found that enhancement of both SERT activity and behavioral despair in the mice depended on the IL-1 cytokine receptor and the signaling protein p38 MAPK.
The findings suggest that the peripheral immune system can trigger despair-like behavior – through IL-1 receptor and p38 MAPK regulation of serotonin signaling – and encourage analysis of this pathway for risk factors in neuropsychiatric disorders.
— Leigh MacMillan
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