April 3, 2009

Aliquots — research highlights from VUMC labs

X-ray of lungs (iStock)

‘PARP for the course’ in B cell survival

B aggressive lymphoma (BAL) proteins are highly expressed in certain types of B cell lymphomas – malignancies of the antibody-producing B lymphocytes. Recently, some BAL proteins have been recognized as poly(ADP-ribose)polymerases (PARPs) – enzymes that modify proteins by adding certain chemical groups. PARPs play a role in DNA damage repair, cell survival and programmed cell death. However, the roles of most of the 17 known PARPs are unclear.

Mark Boothby, M.D., Ph.D., and colleagues demonstrate an important role for one of these proteins: PARP-14, a protein expressed in lymphoid tissues and lymphocyte cell lines. In mice lacking PARP-14, the researchers observed a shift in the proportion of B cells subtypes in the spleen and an impairment of a particular type of antibody response. PARP-14 also mediates the protective effects of the cytokine interleukin-4 on B cell survival after irradiation. The results, reported in the March 12 issue of Blood, establish a role for PARP-14 in B lymphocyte physiology and suggest that BAL-family proteins may influence pathologic processes involving these cells.

Melissa Marino


Lung blood pressure disorder clue

Familial pulmonary arterial hypertension (FPAH) is a progressive, fatal disease caused by mutations in one copy of the BMPR2 gene. Some BMPR2 mutations produce RNA transcripts that are rapidly degraded through the “nonsense-mediated decay” pathway (NMD+). However, only about 20 percent of individuals with NMD+ BMPR2 mutations develop FPAH, suggesting that other factors modify disease risk. Reasoning that levels of normal (or wild-type) transcripts – produced from the remaining normal BMPR2 copy – may also affect disease development, Rizwan Hamid, M.D., Ph.D, and colleagues measured levels of wild-type BMPR2 in cell lines developed from the lymphocytes of NMD+ FPAH patients.

While all subjects had NMD+ mutations, unaffected carriers showed higher levels of wild-type BMPR2 transcripts than FPAH-affected patients, suggesting that variable expression of wild-type BMPR2 plays a role in the development of FPAH. Although the mechanism of this variable expression is unclear, the findings – reported in the April issue of Human Mutation – suggest that agents that increase expression of BMPR2 could be clinically beneficial.

Melissa Marino


Low blood sugar blunts responses

Multiple clinical trials have established the benefits of tight glucose control in the avoidance of diabetic complications. A drawback to aggressive management of blood glucose is an increased frequency of hypoglycemia (low blood glucose), which can impair neurologic functions.

Stephen Davis, M.D., and colleagues investigated the protective “counterregulatory responses” to hypoglycemia in patients with type 2 diabetes before and after six months of intensive therapy to lower A1C values (a measure of average blood glucose control) to near-normal levels. The investigators report in the March issue of Diabetes that these patients had increased numbers of hypoglycemic episodes and blunted counterregulatory responses (endocrine, neuronal and metabolic).

They also demonstrated that prior episodes of hypoglycemia – even at levels considered mild in clinical practice – decreased subsequent physiological responses, suggesting a mechanism for the impaired responses following intensive therapy. The findings reinforce the therapeutic goal of achieving good glucose control while minimizing the occurrence of hypoglycemia.

Leigh MacMillan


New tools for probing neuron chatter

KCC2, a protein that moves potassium and chloride across the neuronal membrane, strengthens inhibitory communication in the nervous system. Genetic studies have suggested that KCC2 may have roles in preventing brain hyperexcitability (the cause of seizures) and in modulating pain information in the spinal cord. But KCC2 function has been difficult to study because there are no potent and specific drugs to block or activate it.To identify compounds that affect KCC2 activity, Eric Delpire, Ph.D., and colleagues developed a fluorescence-based method suitable for high-throughput screening and used it to screen 234,000 small molecules. They identified a large number of molecules that either decrease or increase the activity of KCC2. The researchers report in the Proceedings of the National Academy of Sciences the characterization of a group of inhibitors, further medicinal chemistry efforts to synthesize alternate inhibitors, and analysis of the compounds’ effects on KCC2 function. These new tools will be useful for probing KCC2’s roles in neuronal communication.

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