July 28, 2011

Aliquots: Research highlights from VUMC laboratories

Faulty fatty acids in cystic fibrosis

Cystic fibrosis (CF) results from mutations in the CFTR gene, which causes thick, sticky mucus to build up in the lungs and digestive tract. In addition to these classic clinical features, CF patients often show abnormal levels of fatty acids in their blood and tissues, which may play a role in the pathogenesis of the disease.

Adam Seegmiller, M.D., Ph.D., Michael Laposata, M.D., Ph.D., and colleagues examined the nature of these fatty acid abnormalities using cell culture models of CF. In the journal Lipids, they report that the increases in n-7 (palmitoleate) and n-9 (oleate and eicosatrienoate) fatty acids result from increased expression of metabolic enzymes in the pathways leading to these fatty acids. In Biochimica et Biophysica Acta, they report similar metabolic changes involved in alterations in n-3 (decreased docosahexaenoate) and n-6 (decreased linoleate and increased arachidonate) fatty acids.

Insight into the metabolic mechanisms responsible for these fatty acid abnormalities may improve understanding of what causes CF and lead to improvements in dietary recommendations and therapy for patients with CF.

Melissa Marino


Connecting the dots in schizophrenia

Abnormalities of the hippocampus, a seahorse-shaped brain region involved in learning and memory, may play a role in the psychotic symptoms and cognitive deficits of schizophrenia. Prior studies have suggested that overall hippocampal volume and neuron number are normal in schizophrenia – but whether there are more subtle abnormalities remains unclear.

Using human postmortem brain samples, Christine Konradi, Ph.D., and colleagues compared total number of hippocampal neurons and interneurons (neurons that connect and typically inhibit the action of neighboring neurons) of subjects with schizophrenia to those of unaffected brains. While total hippocampal neuron number was similar, the schizophrenia group showed a significant reduction in the number of neurons expressing somatostatin and parvalbumin – protein markers of interneurons. Levels of mRNA for these markers were also reduced in the schizophrenia group.

The results, reported July 13 in Schizophrenia Research, provide evidence for a specific defect in hippocampal interneurons in schizophrenia and may suggest new targets for drug treatments for the condition.

Melissa Marino


Deciding who’s who in heart valves

Congenital heart valve defects are the leading cause of infant morbidity and mortality. Understanding how valves form during development might provide insight into the processes that go awry in congenital valve disease.
A critical step in early valve formation is the choice an endocardial cell makes between two fates: change types (endocardial to mesenchymal transformation, EMT) and contribute to the valve core, or remain an endocardial cell that can divide and generate the elongated valve leaflet.

H. Scott Baldwin, M.D., and colleagues now report in the July 8 Circulation Research that a transcription factor called Nfatc1, which modulates gene expression, regulates the cell-fate decisions of endocardial cells. The researchers found that Nfatc1 inhibits EMT in the developing valve (by suppressing two factors that initiate EMT). They conclude that Nfatc1 expression levels determine the allocation of endocardial cells to their two fates. The findings suggest that mutations in the Nfatc1 gene may contribute to human congenital heart valve disease.

Leigh MacMillan


Clear vision of protein interactions

The lens of the eye, a transparent tissue that focuses light on the retina, is composed mostly of elongated lens fiber cells. Lens transparency is achieved and maintained by precise cell-cell interactions – disruption of fiber cell packing can lead to light scattering and cataract.

Aquaporin 0 (AQP0) is the most abundant membrane protein in the lens and is thought to function as both a water channel and as a cell adhesion molecule. In the July issue of Investigative Ophthalmology & Visual Science, Zhen Wang, Ph.D., and Kevin Schey, Ph.D., identify cellular proteins that interact with AQP0. Using protein cross-linking reagents and mass spectrometry tools, the researchers show that AQP0 directly associates with ezrin/radixin/moesin (ERM) family members. ERM proteins link cellular actin filaments – components of the cell’s internal “skeleton” – to the cell membrane.

The interaction of AQP0 and ERM proteins may play an important role in fiber cell elongation, cellular architecture, and membrane organization – and disruption of this interaction, for example during aging, could contribute to cataract formation.

Leigh MacMillan

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012