teaching



Resources and information for the planning and delivery of quality instruction



 


Faculty News

Pollocks make list of top nephrology, dialysis professors
Pollocks make list of top nephrology, dialysis professors
UAB professors who developed a new area of translational cardio-renal research are among 15 professors identified as today’s leaders in the field.

pollocksDavid and Jennifer PollockJennifer Pollock, Ph.D., and David Pollock, Ph.D., are among 15 professors identified as today’s leaders in advancing and teaching nephrology and dialysis technology by medicaltechnologyschools.com, which helps students identify the best professors in technology fields.

Together, the Pollocks have developed a brand-new area of translational cardio-renal research through their work with endothelial cells in the kidney blood vessels.

Jennifer Pollock teaches nephrology and kidney studies at UAB and is nationally recognized for both her student mentorship and research, as evidenced by her recent Distinguished Mentor and Scientist Award from the American Physiological Society.

David Pollock also is a past president of the APS and was the recipient of the Louis K. Dahl Award for Hypertension Research from the American Heart Association in 2013. He recently visited Cuba with an APS delegation towith leaders of the Cuban Society of Physiological Sciences.

The Pollocks joined UAB in 2014 to build the new cardio-renal program.

Molecular study points to possible therapy for autoimmune disease
Molecular study points to possible therapy for autoimmune disease
The challenge is to stifle the binding of inhibitory antibodies but retain activity of a blood enzyme.

Long ZhengLong ZhengA rare autoimmune disease creates sudden pain in the abdomen or the head, sending a patient to the emergency room with a potentially fatal condition. The pain comes from a multitude of blockages of tiny blood vessels, formed after the patient’s own immune system somehow inhibits an enzyme that is vital to control clotting.

The syndrome is called thrombotic thrombocytopenic purpura, or TTP, and treatment involves exchanging three to seven liters of plasma each day, at a cost of $10,000 a day. This costly care may continue for several weeks or months.

Long Zheng, M.D., Ph.D., the Robert B. Adams Endowed professor and director of the Division of Laboratory Medicine at the University of Alabama at BirminghamDepartment of Pathology, wants to create a faster and more effective treatment for these patients. This has led Zheng and colleagues to molecular-level studies of the antibody that inactivates a blood enzyme, called ADAMTS13. ADAMTS13 recognizes and cuts a blood adhesion protein called von Willebrand factor. The inhibition of ADAMTS13 activity by the antibody in TTP patients allows ultra-large von Willebrand factor to form disseminated microvascular clots.

The ability of ADAMTS13 to recognize von Willibrand factor is exquisitely sensitive, somewhat like a fan who goes to a football game with 50,000 people and yet recognizes his cousin out of all the faces in the crowd. Similarly, the ability of the autoimmune antibodies in a TTP patient to recognize and bind to the patient’s own ADAMTS13 enzyme is also exquisitely sensitive, picking only ADAMTS13 out of all the other possible “self” proteins in the body.

Learning the molecular details of these two recognition abilities will help Zheng subtly alter ADAMTS13, to produce a therapeutic enzyme that can elude recognition by the autoimmune antibodies, yet still retains its activity to cleave von Willebrand factor. Such an engineered enzyme could be given to TTP patients in the hospital to speed recovery and slash the cost of treatment.

In a paper published in the Proceedings of the National Academy of Sciences, “High Resolution Epitope Mapping by HX MS Reveals the Pathogenic Mechanism and a Possible Therapy for Autoimmune TTP Disease,” senior author Zheng and colleagues report on those molecular details. The results reveal, for the first time, the mechanism of the inhibition of ADAMTS13 by autoantibodies and suggest an avenue for therapeutic intervention.

“This was really surprising. It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

The researchers found that five small loops in the protein’s amino acid sequence are necessary for the autoantibodies to bind to ADAMTS13. Cutting or substituting several amino acids out of any single one of the five loops prevented binding; furthermore, those small deletions in any single one of the five small loops also left the enzyme unable to cut von Willebrand factor.

“This was really surprising,” Zheng said. “It’s like a table with five legs. If you take one away, it should still stand, but somehow it collapsed. This suggests that you need the coordinated activity of all five.”

Thus, it appears that the autoimmune antibodies in TTP patients inhibit the enzyme by physically blocking the recognition site of ADAMTS13 for von Willebrand factor. More importantly, analysis of autoantibodies from 23 more TTP patients found that most use the same binding site, suggesting that a modified ADAMTS13 enzyme by protein engineering may be able to help a wide range of TTP patients.

Details of the research

The five years of research for this paper included the labs of Don L. Siegel, M.D., Ph.D., an expert in phage display, and S. Walter Englander, Ph.D., father of hydrogen exchange/mass spectrometry analysis to measure the protein-protein interaction regions of large proteins. Both Siegel and Englander are at the Perelman School of Medicine at the University of Pennsylvania, where Zheng used to work before moving to Birmingham.

The researchers first isolated messenger RNAs that code single chains of variable region of the monoclonal antibodies from B cells of patients with acquired TTP. They used a technique called phage display to select the messenger RNAs that code specific antibodies that bind and inhibit ADAMTS13. These monoclonal antibodies are then expressed in E. coli cells, purified, and biochemically characterized.

Of these, three inhibitory monoclonal antibodies were selected for further study by hydrogen-deuterium exchange coupled with mass spectrometry. This technology uses amine hydrogen (in H2O) exchange with deuterium (D2O) on each amino acid residue except proline. After reaction was stopped, the protein was then cut into small pieces (or peptide fragments) and run through HPLC for separation and mass spectrometry for identification. Antibody binding sites were detected by their ability to block the hydrogen and deuterium exchange, as compared with ADAMTS13 that was unbound.

One of the three high-affinity probes selected by phage display was used for the competition experiments against polyclonal autoimmune antibodies from 23 TTP patients. The results demonstrate that this particular binding epitope is common among patients with acquired autoimmune TTP.

Besides Zheng, co-authors are Veronica Casina, Wenbing Hu, Jianhua Mao, Rui-Nan Lu, Hayley Hanby, Brandy Pickens, Zhongyuan Kan, Woon Lim, Leland Mayne, Eric Ostertag, Stephen Kacir, Don Siegel and S. Walter Englander, all of the University of Pennsylvania. Zheng was recruited to UAB from the University of Pennsylvania in February and is the inaugural holder of the Robert B. Adams Endowed Professorship in Pathology in the UAB School of Medicine.

Rowe named head of UAB Cystic Fibrosis Center
Rowe named head of UAB Cystic Fibrosis Center
The CF clinical trials expert will take the reins of the UAB Gregory Fleming James Cystic Fibrosis Center on Aug. 1.

steven roweSteven M. Rowe, M.D., MSPH, professor in the Division of Pulmonary, Allergy and Critical Care Medicine, has been named director of the Gregory Fleming James Cystic Fibrosis Research Center in the University of Alabama at Birmingham School of Medicine effective Aug. 1.

Rowe is an expert in the design and conduct of clinical trials targeting the basic CF defect. He says being tapped to lead the center is an exciting opportunity to build on the long legacy of cystic fibrosis research at UAB.

“It’s an incredibly exciting time to be in CF research, and researchers at UAB have been a big part of that progress,” Rowe said. “There have been two new treatments approved in the last three years that address the basic defect that causes CF, so we’re changing the face of the disease now for a large proportion of patients. And with the discovery of these new treatments, researchers have a clear path as to what we need to do next to help find a cure.”

CF is a chronic genetic disorder of the body’s mucus glands that can cause severe or even fatal respiratory infections in children and young adults. Approximately 30,000 people in the United States have CF, according the National Institutes of Health. 

The UAB CF center was established in 1981, with the mission to provide a comprehensive, multidisciplinary understanding of CF pathogenesis, advance innovative therapies and, ultimately, identify a cure for the disease. Center membership is made up of over 25 faculty from seven UAB schools and more than 25 departments.

Announcements

Video Reports