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Research News

REGARDS data show diabetics who use verapamil have lower glucose levels
REGARDS data show diabetics who use verapamil have lower glucose levels
Lead author of paper published in Diabetes Research and Clinical Practice journal says, while causal relationship cannot be inferred, findings are “absolutely encouraging.”

yulia khodnevaA new University of Alabama at Birmingham research paper published in the journal Diabetes Research and Clinical Practice shows for the first time that there is an association of verapamil use and lower fasting glucose levels in humans with diabetes. It is a promising finding at UAB, where the Comprehensive Diabetes Center is currently conducting a first-of-its-kind, JDRF-funded clinical trial using verapamil, a drug that researchers in the School of Medicine have shown completely reverses the disease in mice models.

Yulia Khodneva M.D., Ph.D., a research associate and postdoctoral scholar in UAB’s Division of Preventive Medicine and junior member of the Comprehensive Diabetes Center, examined the association of calcium channel blockers and verapamil use with fasting serum glucose among almost 5,000 adults with diabetes who were part of the REGARDS study. The Reasons for Geographic and Racial Differences in Stroke project, sponsored by the National Institutes of Health, is a national study focusing on learning more about the factors that increase a person’s risk of having cardiovascular disease.

The sample of diabetic adults included 1,484 calcium channel blocker users, of whom 174 were verapamil users. The findings showed that calcium channel blocker users had 5 mg/dL lower serum glucose compared to non-users. Verapamil users had on average 10 mg/dL lower serum glucose compared to calcium channel blocker non-users. And the numbers showed a substantially greater difference among insulin users who also took verapamil. Verapamil users who took insulin in combination with oral medication had a 24 mg/dL lower serum glucose, and verapamil users who took insulin alone to manage their diabetes showed a 37 mg/dL lower serum glucose.

“This is a cross-sectional observational study unlike the current prospective randomized UAB verapamil clinical trial, so we can’t infer causal relationship between using verapamil and lower glucose levels; but we can say there is an association with lower glucose levels, and that is absolutely encouraging,” Khodneva said.

About the verapamil clinical trial

  • Recruitment for the UAB verapamil clinical trial began in early 2015.
  • The trial will enroll 52 people between the ages of 19 and 45 within three months of receiving a diagnosis of type 1 diabetes. MORE ENROLLEES ARE NEEDED.
  • Patients enrolled will be randomized to receive verapamil or a placebo for one year while continuing with their insulin pump therapy.
  • Patients will receive a continuous glucose monitoring system that will enable them to measure their blood sugar 24 hours a day, seven days a week.
  • Talk to your primary care physician if you are experiencing excessive thirst, excessive urination or unwanted weight loss in association with fatigue.
  • For more information or to enroll, contact UAB at 205-934-4112 or T1DM@uab.edu. To speak to a physician, contact Fernando Ovalle, M.D., at 205-934-4171.
  • Support this and other diabetes research at UAB by visiting the Comprehensive Diabetes Center.

Khodneva says the findings in the final subgroup, which used insulin alone and included participants who had mostly Type 1 or severe Type 2 diabetes, were quite striking.

“The change in glucose for that group compared to those not taking verapamil — 37 mg/dL — is almost four times higher than when you look at the whole sample of diabetic adults,” Khodneva said. “That made us think that verapamil is predominantly active for participants who have Type 1 diabetes or those with Type 2 diabetes who have really damaged beta cells. There seems to be something that works on the structural level, especially for those who have stronger beta-cell damage.”

“Dr. Khodneva has done a tremendous job analyzing these large data sets and discovering for the first time that verapamil use is associated with lower glucose levels in patients with diabetes,” said Anath Shalev, M.D., director of UAB’s Comprehensive Diabetes Center and principal investigator of the verapamil clinical trial. “Strikingly, the observed difference in glucose levels is comparable to an approximately 1 percent reduction in HbA1C and to what would be expected from the addition of an approved diabetes drug. Moreover, the large difference in glucose levels especially in the groups taking insulin is consistent with our underlying hypothesis that verapamil promotes functional beta-cell mass.”

UAB announced its verapamil clinical trial in November 2014 and began enrolling patients in January 2015. The first results that will assess verapamil’s effectiveness on Type 1 diabetes are still approximately 18 months away.

The trial is testing an approach different from any current diabetes treatment by focusing on promoting pancreatic beta cells, which produce insulin the body needs to control blood sugar. UAB scientists have proved through years of research that high blood sugar causes the body to overproduce a protein called TXNIP, which is increased within the beta cells in response to diabetes, but had never previously been known to be important in beta-cell biology. Too much TXNIP in the pancreatic beta cells leads to their death and thwarts the body’s efforts to produce insulin, thereby contributing to the progression of diabetes.

But UAB scientists have also uncovered that verapamil, which is widely used to treat high blood pressure, irregular heartbeat and migraine headaches, can lower TXNIP levels by decreasing calcium concentration in the beta cells — to the point that, when mouse models with established diabetes and blood sugars above 300 milligrams per deciliter were treated with verapamil, the disease was eradicated. See an animation of how this works here.

The trial will enroll 52 people between the ages of 18 and 45 who are within three months of receiving a diagnosis of Type 1 diabetes. More than 20 people have enrolled so far, and more participants are needed. For more information or to enroll, contact UAB at 205-934-4112 or T1DM@uab.edu.

UAB researchers identify protein that plays key role in brain cancer stem cell growth and survival
UAB researchers identify protein that plays key role in brain cancer stem cell growth and survival
New UAB research study shows therapeutic promise in targeting MLK4 in brain cancer patients.
nakano labFront row, from left: Ichiro Nakano, Sunghak Kim, Terry Hamby, Tesha Sherpa, Mutsuko Minata, Shinobu Yamaguchi; Back row: Jun Wan, Zhuo Zhang, Svetlana Komarova, Marat Pavliukov, Jia Wang

A team of physicians and scientists at the University of Alabama at Birmingham discovered that a kinase protein, mixed lineage kinase 4, also known as MLK4, plays a crucial role in survival of patient-derived brain cancer stem cells in pre-clinical animal models. The findings suggest that MLK4 could potentially be a useful target for cancer treatment.

Protein kinases are key regulators of cell function that constitute one of the largest and most functionally diverse gene families. Until recently, MLK4 was considered a poorly characterized kinase. The UAB team, however, identified this gene from a stepwise screening of molecules that are elevated in cancer stem cells isolated from brain cancer patients.

The findings, published this week online in Cancer Cell, nailed down the novel molecular mechanisms for which MLK4 is essential in cancer stem cells and not in normal cells in the human body. Most importantly, brain cancer patients with higher MLK4 expression have shorter survival despite the current intensive therapies including surgery, chemotherapy and radiotherapy. Nonetheless, there are no MLK4-targeting therapies or clinical trials currently available for patients.

“There is no doubt that society desperately needs new and effective therapies for this life-threatening brain disease. Improvement of patient survival for the past 50 years has been counted by months and not years,” said Ichiro Nakano, M.D., Ph.D., professor in the UAB Department of Neurosurgery and principal investigator of the study. “We, as an international collaborative team centered at UAB, focus on cancer stem cells as a therapeutic target in brain cancers.”

“There is no doubt that society desperately needs new and effective therapies for this life-threatening brain disease. Improvement of patient survival for the past 50 years has been counted by months and not years. We, as an international collaborative team centered at UAB, focus on cancer stem cells as a therapeutic target in brain cancers.”

In early 2000, Nakano was involved in a team that isolated cancer stem cells from brain cancers at the University of California at Los Angeles. This discovery gained attention from physicians and scientists because accumulating evidence suggested that cancer stem cells are relatively therapy-resistant and appear to contribute to re-generation of recurrent tumors that subsequently kill affected patients.

“Cancer stem cells share many of the properties of normal stem cells but have also gained transformed cancerous phenotypes,” said Sunghak Kim, Ph.D., an instructor in the UAB Department of Neurosurgery who has led much of the research. “We have been trying to identify the cancer stem cell-specific Achilles heel that could make all the difference.”

While conducting this study, the investigators also found that MLK4-high tumors appear to have Mesenchymal signature, considered to be one process cancers use to become aggressive and therapy-resistant.

“Approximately 35 to 40 percent of glioblastoma patients appear to have Mesenchymal signature. It is also interesting that some non-Mesenchymal cancers seem to shift their phenotype to a Mesenchymal one after therapeutic failure,” Kim said. “We are still collecting more data on this additional piece of information to prove that this is a universal event in brain cancers.”

It is important to note that MLK4 is not expressed in all brain cancers. But now that research indicates that MLK4 is elevated in a subset of brain cancer patients and plays a key role in brain cancer stem cell growth, the next step is to identify targeted therapies that affect the MLK4 in the cancer stem cells.

“We have begun to collaborate with Southern Research Institute to screen drug candidates that selectively target MLK4 in brain cancers,” said Nakano, also a senior scientist at the UAB Comprehensive Cancer Center. “Targeting strategies for MLK4 may work for other cancer types, as we already know that MLK4 is highly expressed in some other malignant types of cancers.”

Nakano added, “Ultimately, we want better outcomes for patients with brain cancer. There’s no question that this is not an easy battle. But by further understanding the molecular mechanisms and applying new targeted therapeutic strategies including MLK4, we are hoping to provide brain cancer patients with more promising and tailored therapeutic approaches.”

Collaborative participants on this project include M.D. Anderson, Ohio State University, University of Texas, Northwestern University, Cincinnati Hospital Medical Center, and a variety of German and Japanese research departments and institutes.

The work was supported by the American Cancer Society, the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science and Takeda Science Foundation.

Fixing published research mistakes not easy; fixing the publishing system may be harder
Fixing published research mistakes not easy; fixing the publishing system may be harder
Articles in peer-reviewed research journals sometimes have mistakes, and a UAB study shows the process to correct such mistakes is flawed.

correction processA commentary published today in Nature suggests that the process for fixing mistakes in peer-reviewed research articles is flawed. The article, written by scientists at the University of Alabama at Birmingham, points out that journals are slow to respond and even slower to take action when questions regarding the accuracy of a published research paper are raised.

The authors say that, in the course of assembling weekly lists of articles on obesity and nutrition, they began to notice more peer-reviewed articles containing what they refer to as ‘substantial or invalidating errors.’ “What was striking was how severe some of these errors were, involving mathematically impossible values, probabilities greater than one, weight loss results that, if true, would have required that adults had grown over 6 centimeters in height in two months, to name just a few,” said David B. Allison, Ph.D., leader of the research team and associate dean for Science in the UAB School of Public Health.

“These errors involved factual mistakes or practices which veered substantially from clearly accepted procedures in ways that, if corrected, might alter a paper’s conclusions,” said Andrew Brown, Ph.D., a scientist in the UAB School of Public Health and co-author of the commentary. “In several cases, our noting these errors led to retractions of the papers containing them.”

Brown says the team attempted to address more than 25 of these errors with letters to authors or journals. Their efforts revealed invalidating practices that occur repeatedly and showed how journals and authors react when faced with mistakes that need correction.

“We learned that post-publication peer review is not consistent, smooth or rapid,” Allison said. “Many journal editors and staff seemed unprepared to investigate, take action or even respond. Too often, the process spiraled through layers of ineffective emails among authors, editors and unidentified journal representatives, often without any public statement’s being added to the original article.”

During the informal 18-month review of literature, the authors found a number of recurring problems:

  • Editors are often unprepared or reluctant to take speedy and appropriate action
  • Where to send expressions of concern is unclear
  • Journal staff who acknowledged invalidating errors were reluctant to issue retractions or even timely expressions of concern
  • Some journals may charge fees to authors who report the issues to correct others’ mistakes (more than $1,000)
  • No standard mechanism exists to request raw data for review to confirm the errors
  • Concerns expressed through online forums are easily overlooked and are not connected in a way to be found by readers of the article in question
The authors observed that there is little formal guidance for post-publication corrections. They recommend that journals should standardize their submission and peer-review processes, establish clear protocols to address expressions of concern, and waive publication fees associated with those expressions of concern.

The authors observed that there is little formal guidance for post-publication corrections. They recommend that journals should standardize their submission and peer-review processes, establish clear protocols to address expressions of concern, and waive publication fees associated with those expressions of concern.

Further suggestions include creating an environment to address readers’ concerns rapidly and provide clear information on how and to whom such concerns should be addressed.

“We also think it is very important to create an understanding that such expressions of concern are not a condemnation of the work, but should be viewed as an alert that the work is undergoing further scrutiny,” said co-author Kathryn A. Kaiser, Ph.D.

Additional recommendations suggest journals and statistical experts should work together to identify common statistical mistakes and that authors and journals should be prepared to share data and analysis code quickly when questions arise.

The authors noted common statistical errors in many of the studies, including mistaken design or analysis of cluster randomized trials, miscalculation in meta-analyses, and inappropriate baseline comparisons.

The authors acknowledge that their work did not constitute a formal survey and suggest that a more formal, systematic survey is needed to establish whether their experiences are representative of science in general.

“Ideally, anyone who detects a potential problem with a study will engage, whether by writing to authors and editors or by commenting online, and will do so in a collegial way,” Brown said. “Scientists who engage in post-publication review often do so out of a sense of duty to their community, but this important work does not come with the same prestige as other scientific endeavors.”

“Robust science needs robust corrections,” Allison added. “It is time to make the process less onerous.”

Co-authors of the commentary are Brown, Allison, Kaiser and Brandon J. George, Ph.D., of the UAB School of Public Health.

UAB researchers work to unravel the complex genetic disease neurofibromatosis type 1
UAB researchers work to unravel the complex genetic disease neurofibromatosis type 1
One major goal is the discovery of new genotype/phenotype correlations — how a particular mutation indicates that some symptoms in patients are unlikely to develop with age.
ludwine messiaenLudwine Messiaen

It is easy to tell a medical research story that has a simple and dramatic moment. But disease is often much more complex, and the work to understand it can be painstaking.

A vivid example of that is seen in the UAB Medical Genomics Laboratory, headed by Ludwine Messiaen, Ph.D., professor of genetics. This lab offers clinical genetic testing for a broad array of common and rare genetic disorders. One of the most confounding is neurofibromatosis type 1.

This can be a heartbreaking disease.

Changes at puberty

It usually starts with café-au-lait skin markings, so named because of their distinctive coloring, in an infant. But at puberty — already a challenging time in a person’s life, many patients develop benign skin tumors called neurofibromas that erupt as bumps across the body. Patients vary widely in their symptoms, which can include freckles near skin folds of the body, nodules in the eyes, tumors along the optic nerve, heart defects, anomalies of connective tissue or bones, developmental delay, intellectual disability, and learning problems.

Patients show a broad clinical variability as they grow, and whether their case will be mild or severe cannot — in most cases — be predicted when the disease first appears. This leaves physicians and families uncertain about what symptoms will appear in a particular child as he or she nears puberty.

cal spotCafe-au-lait skin markings on the back of a young child

Profusion of mutations

This kaleidoscope of clinical signs is mirrored by an abundance of different mutations in the NF1 gene, responsible for the disease. The UAB Medical Genomics Laboratory has collected DNA and identified a pathogenic mutation in more than 7,800 unrelated neurofibromatosis type 1 patients. All have NF1 mutations, but meticulous examination has revealed so far more than 3,000 different mutations. These can be found in every part of the gene, and the mutational spectrum involves microdeletions, deletions or duplications that involve one or more exons, frameshift and nonsense mutations, and splice or missense mutations. Almost half of the NF1 patients carry a unique mutation found only in their specific family. Other mutations have been found in multiple unrelated families.

Two searches

From this complicated array of mutations and clinical symptoms, Messiaen and her colleagues have tried to answer two questions.

First, can a particular mutation be correlated with the symptoms that will develop as the child grows? This is called a genotype/phenotype (DNA/symptoms) correlation, and only two have previously been found for neurofibromatosis type 1.

“It’s important for people to know what may happen,” Messiaen said. “When a child is born with neurofibromatosis type 1, café-au-lait spots appear very shortly after birth; but other problems, more specifically the development of skin neurofibromas, typically appear around puberty. If a genotype/phenotype correlation exists for a particular mutation, it will help these families have some perspective of what the future will bring, and it will help families cope with the disease. If it is a mutation that takes away the heavy tumor burden at puberty, that information will relieve families, even though learning disabilities may still appear.”

The second question for Messiaen and UAB postdoctoral trainee Meng-Chang “Jack” Hsiao, UAB Department of Genetics, is whether they could identify the likely mechanism that caused a group of mutations in which the DNA has been rearranged to create mix-ups that make the gene longer or shorter.

Each question requires meticulous research. One means reaching out to patients, families and referring physicians around the nation and the world. The other is a molecular genetic detective story, pursued in the UAB lab.

ludwine mengMessiaen and Meng-Chang "Jack" Hsiao are exploring the mechanisms behind the mutations seen in neurofibromatosis type 1.

Seeking a correlation

For the first question, Messiaen last year led a group of 74 researchers and clinicians from 58 centers in the discovery of just the third genotype/phenotype correlation ever found for neurofibromatosis type 1. They looked at 136 individuals who all had a missense mutation in the arginine moiety of neurofibromin, the protein encoded by the NF1 gene, at amino acid position 1,809. These mutations are the second-most-frequent ones seen in the UAB collection.

To look for a correlation, the team had to gather detailed clinical symptomatic information for each of the neurofibromatosis patients, from patients, families, referral physicians and researchers in 24 U.S. states and Australia, Belgium, Brazil, Chile, the United Kingdom, India, Israel and Spain.

In a paper published in the journal Human Mutation last year, they found that these patients have a distinct phenotype, Messiaen says. They had the café-au-lait marks, with or without the skin-fold freckling and Lisch eye nodules. But the patients did not develop the visible, disfiguring neurofibromas on their skin around puberty. However, there was a higher prevalence of blood flow obstruction from the heart to the lungs and a short stature. More than half had developmental delays and/or learning disabilities.

Messiaen is calling for international collaboration to expand the study to a total of 250 mutations, which will provide the statistical power needed for patient case management by doctors. And in the next few years, she will focus on finding more genotype/phenotype correlations for other specific mutations.

"If a genotype/phenotype correlation exists for a particular mutation, it will help these families have some perspective of what the future will bring, and it will help families cope with the disease."

"If a genotype/phenotype correlation exists for a particular mutation, it will help these families have some perspective of what the future will bring, and it will help families cope with the disease."

Chasing molecular clues

For the second question, Hsiao, Messiaen and colleagues looked at NF1 copy-number variations — where the mutant gene is either longer or shorter than a normal NF1 gene — from 85 unrelated neurofibromatosis type 1 patients, along with two previously published copy-number variations. Ten of these were partial duplications within the NF1 gene, and 77 were deletions. Hsiao looked for specific nucleotide breakpoints in these variants — the places where the duplication or deletion begins or ends — that would be clues to how the changes occurred.

The methods to examine these mutant genes include multiplex ligation-dependent probe amplification, array comparative genomic hybridization, breakpoint-spanning PCR and sequencing.

“The most difficult challenge is to see how the rearrangements happen,” Hsiao said. “It’s really difficult to decipher.”

In a paper published in The American Journal of Human Genetics last year, Hsiao found that DNA replication-based mechanisms — such as fork stalling and template switching, and microhomology-mediated break-induced replication — as well as serial replication stalling appear to be the major causes of the NF1 copy-number variants. In one complicated rearrangement, the DNA replication appeared to have stalled five times, with the stalled DNA strand then either invading forward or invading backward into another part of the NF1 gene. Hsiao also found that the mutant genes showed rearrangement hotspots that included one palindromic sequence and four Alu elements. Alu elements are short primate-specific repeats in the DNA; the human genome contains about 1 million copies of various Alu elements that make up almost 11 percent of the genome.

Two sides to the research

Messiaen says the two recent papers are “nice companions.”

“They show two sides of research aspects of this laboratory,” she said. “One digs deeper into the mechanism of specific types of mutation, and one contributes to genotype/phenotype correlation.”

2016 Darwin Day commemorates Charles Darwin’s birthday, showcases scientific research
2016 Darwin Day commemorates Charles Darwin’s birthday, showcases scientific research
Poster sessions and guest lecturers aim to celebrate Darwin’s legacy.

darwin day 2016To honor the 207th birthday of legendary evolutionary biologist Charles Darwin, the University of Alabama at Birmingham will host its annual Darwin Day on Thursday, Feb. 11, and Friday, Feb. 12. The events will celebrate scientific research in evolutionary biology and other disciplines.

The event is co-hosted by UAB’s departments of Anthropology and Biology in the College of Arts and Sciences.

“Charles Darwin’s great discovery, the principle of natural selection, is more relevant to science than ever before,” said Steven Austad, Ph.D., chair of the Department of Biology. “For instance, it underlies our increasing success in cancer chemotherapy, provides guidance in combating new strains of drug-resistant diseases, and will ultimately determine how catastrophic climate change will prove to be for our planet.”

A panel discussion exploring evolution, belief and education will kick off this year’s Darwin Day events in Lister Hill Library’s Edge of Chaos.The panel, which will be led by guest speakers Elisabetta Palagi, Ph.D., a behavioral biologist from the Natural History Museum University of Pisa in Italy, and Josh Rosenau, an evolutionary biologist from the National Center for Science Education, will take place from 2-3:30 p.m. on Feb. 11. Lee Meadows, Ph.D., from UAB’s School of Education, and Marshall Abrams, Ph.D., a philosophy professor in UAB’s College of Arts and Sciences, will also be panelists for this discussion.

Following the panel, students and faculty will present a public poster session highlighting exciting new research from 3:30-4:30 p.m. at the Edge of Chaos. Those interested in presenting a poster should send an email to darwinday@uab.edu with their name, department, poster title, and indication of whether they are a student, postdoc or faculty.

“Anthropologists and other students of science today will be well-served by striving to emulate Darwin’s objectivity, meticulous attention to detail and appreciation for complexity during the practice of science.”

On Thursday evening, Darwin Day activities will continue with a reception followed by a talk by Rosenau. Rosenau’s lecture, “The Impact of Darwin in Everyday Life,” will begin at 7 p.m. following the 6 p.m. reception at the McWane Science Center and is open to the public.  

Darwin Day will continue on Friday, Feb. 12, from 4 to 5 p.m., with a lecture from Palagi. Palagi’s talk, “The Strategic Functions of Play: Modality and Communication,” will be held in Heritage Hall, Room 104.

“The approach of Charles Darwin represents the scientific endeavor at its best wherein data and reasoning interact to elucidate the natural world,” said Doug Fry, Ph.D., chair of the Department of Anthropology. “Anthropologists and other students of science today will be well-served by striving to emulate Darwin’s objectivity, meticulous attention to detail and appreciation for complexity during the practice of science.”

Refreshments and drinks will be provided at all events, and Darwin Day T-shirts will be on sale as well. For more information about the events, email darwinday@uab.edu.

Sponsors for the 2016 Darwin Day include the UAB Honors College and the Endowment for the John S. Jemison, Jr., Visiting Professorship in the Humanities.

Integrated Research Administration Portal (IRAP)



  • IRAP is the integrated portal which will support the electronic submission of funding applications and compliance forms for future research initiatives.
  • Visit this site to see the suite of modules available.

 

IRAP