The recipient of this prestigious annual award will receive a $5,000 award and will be the keynote speaker at the DFL reception to be held in their honor.
Nominations for the 2014 Distinguished Faculty Lecturer Award are now being accepted. To be eligible for this prestigious annual award, an individual must be a full-time, part-time, or emeritus member with a primary or secondary appointment of the faculty of the Academic Health Center, or a University Professor who has:

  • Advanced the frontiers of science or otherwise made a significant contribution to the health of people, or
  • Made an outstanding contribution to the Academic Health Center through education, research, or public service.

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Faculty News

UAB researcher probes role of a master gene in skeletal formation
UAB researcher probes role of a master gene in skeletal formation
The runx2 master transcription factor functions differently in chondrocytes and osteoblasts, two key cells in bone formation.

merck 1Amjad Javed and Haiyan Chen examine the effect of a runx2 deletion on bone mineralization.

Amjad Javed, Ph.D., of the University of Alabama at Birmingham, has taken a major step forward in understanding the bone development function of a gene called runx2, which could lead to future ways to speed bone healing, aid bone bioengineering, stem osteoporosis and reduce arthritis.

Javed, a professor in the UAB School of Dentistry’s Department of Oral and Maxillofacial Surgery, says the results will contribute to future personalized medicine. This month, Javed presented this work to a standing-room-only audience at the International Association for Dental Research Annual Meeting in Boston. The work was published recently in two articles in the Journal of Bone and Mineral Research.

It was well-known that the deletion of both copies of the runx2 gene is lethal and the organism cannot form bone, teeth or cartilage.

To learn about the function of runx2 in specific cells types, Javed and his colleagues developed mice in which both copies of the runx2 gene were removed in only one of two key cells for bone tissue — either chondrocytes or osteoblasts.

“Our objective was to dissect and tease out which cell is really contributing what in bone development,” Javed said. “Runx2 is vital. But when we talk up personalized medicine, we need to identify which specialized cells to target within bone tissue.”

Study of these mice (technically known as the next-generation conditional knockout runx2 model) shows that chondrocytes and osteoblasts have surprisingly different functions in bone formation during gestation or after birth:

  • Chondrocytes are involved in bone mineralization during embryonic development.
  • Osteoblasts are involved in bone growth during postnatal developmentThis is a major step forward in understanding the biology of bones — the dynamic, complex organs that are actively remodeled throughout life. Bones have cartilage-producing cells (chondrocytes), bone-creating cells (osteoblasts), bone-eating cells (osteoclasts), neuronal cells and blood-forming (hematopoietic) cells. Connective tissue and muscle surround the bones.

merck 1A chondrocyte specific runx2 homozygous mouse at embryogenesis period E18 (right) has cartilage tissue (stained light blue) but a nearly complete lack of endochondral ossification (the purple stain seen in the control mouse, left). This lack of bone mineralization is especially noticeable in the spinal column, ribs and legs that are initially generated by chondrocytes.

Chondrocytes

Javed’s model began with the cartilage-producing cells. “We first removed the runx2 gene in chondrocytes, cells that are fundamental for every cartilage tissue in the body,” Javed said. “Our first surprise was lethality at birth.”

The skull of the mouse neonates was normal (skull bones are formed through a different bone-creation process); but the cartilage of all the other bones in the body failed to mature and get replaced by mineralized bone, a process known as endochondral ossification. So runx2, which had previously been thought to function only in the developing terminally mature chondrocyte, now appears to act earlier.

Without the runx2 gene, chondrocytes are unable to proliferate and differentiate into the column of cells needed for bone formation and lengthening. The deletion mutant showed that runx2 directly regulates a unique set of four cell-cycle genes to control the proliferative capacity of chondrocytes. The runx2 mutant mice also suffered dwarfism due to a near absence of a proliferative zone in the growth plates of bones.

Osteoblasts

When Javed’s group removed runx2 in osteoblast cells, the results were again surprising. “Here we expected lethality,” Javed said. “To our surprise, they were born alive. When we saw that, we thought it was a mistake. We started questioning, ‘What happened?’”

It had been thought that the runx2 mutation would prevent the osteoblasts from differentiating into their final developmental stage of mature osteoblasts, and thus leave the mice boneless. But the results showed that the runx2 gene is not essential after the cells have already committed to becoming mature osteoblasts. Thus, most of the bones of the mice developed normally, though they had poor calcification.

The exception was the skull, which is formed through a different bone-creation process (intramembranous ossification). The skulls of the runx2 mutant mice had open fontanelles and sutures — the soft spots of the head between the six plates of the skull, spots that are supposed to fuse into bone after birth. Open fontanelles are one of the hallmarks seen in the human hereditary congenital disorder cleidocranial dysplasia (CCD), caused by a heterozygous runx2 mutation; but the mice did not show the other hallmark of human CCD, a missing collarbone. Lacking a collarbone, CCD patients are able to touch their shoulders together in front of their chest.

“Then, we had an additional surprise,” Javed said of the mice with runx2 deletion in osteoblasts. “It is the postnatal skeletal growth that is affected. The mouse starts normally, but by three months of age — which is equivalent to 18-21 years in humans — the mice had 30 percent less weight than wild-type mice.”

The runx2 mutation in osteoblasts caused poor alignment of the collagen scaffold that provides structural strength to mineralized bone. This left the bones brittle, less stiff and prone to fractures. As an additional surprise, the runx2 mutation in osteoblasts caused a significant reduction in osteoclasts (the bone-eating cells that work together with osteoblasts in bone remodeling).

The runx family

Runx2 — as well as two related genes called runx1 and runx3 — is a master transcription factor that controls at least a thousand other genes. The developmental impact of these runx genes (pronounced either “runks” or “run-ex”) has long been known by making deletion mutants of each gene. These deletion-mutants are lethal during gestational development, but each master transcription factor controls a very different tissue.

While runx2 controls bone, teeth and cartilage, organisms with loss of the runx1 gene suffer problems in hematopoiesis. A deletion of runx3 gene leads to hyperplasia of the gastrointestinal tract.

Javed’s colleagues in the runx2 work, which took three years to fully develop and test, are Haiyan Chen, M.D., Ph.D., Farah Ghori-Javed, M.D., Harunur Rashid, Ph.D., Mitra Adhami Ph.D., and John Clarke, all of the Department of Oral and Maxillofacial Surgery, Institute of Oral Health Research in the UAB School of Dentistry; Rosa Serra, Ph.D., of the UAB Department of Cell, Developmental and Integrative Biology, UAB School of Medicine; Yang Yang, M.D., Ph.D., of the UAB Division of Molecular and Cellular Pathology, UAB Department of Pathology in the UAB School of Medicine; and Soraya Gutierrez, Ph.D., of the Universidad de Concepción, Chile, Departamento do Bioquímica y Biología Molecular.

The papers are “Runx2 regulates endochondral ossification through control of chondrocyte proliferation and differentiation” and “Loss of runx2 in committed osteoblasts impairs postnatal skeletogenesis.”

 

School of Nursing research shows 'culture shift' needed for palliative care
School of Nursing research shows 'culture shift' needed for palliative care

Early palliative care offers statistically beneficial effects on patient survival and family caregiver burden, according to articles published in the Journal of Clinical Oncology.

palliativenursingTwo papers recently published by University of Alabama at Birmingham School of Nursing researchers in the Journal of Clinical Oncology highlight the need for a “culture shift” by clinicians and the general public to engage palliative care services long before a person reaches the final stage of life.

Two articles reporting on 207 advanced cancer patients and 122 of their family caregivers who participated in the ENABLE III Trial (“Early Versus Delayed Initiation of Concurrent Palliative Oncology Care” and “Benefits of Early Versus Delayed Palliative Care to Informal Family Caregivers of Patients With Advanced Cancer”) reveal that palliative care delivered soon after a diagnosis of advanced cancer had statistically beneficial effects on patient survival and family caregiver depression and burden when compared with care provided 12 weeks later. The one-year survival rate for patients was 63 percent for those who received early palliative care, compared with 48 percent in the group whose care was delayed. These results support integration of palliative care for patients and families as soon as possible after diagnosis.

“Palliative care is about providing an extra layer of support so that patients can live well and families can be supported,” said principal investigator Marie Bakitas, D.N.Sc., professor and Marie L. O’Koren Endowed Chair in the School of Nursing. “These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”

“If patients and clinicians wait to introduce palliative care when a person is actively dying, it limits the full range of services that patients and their families can receive,” said Nick Dionne-Odom, Ph.D., postdoctoral fellow in the School of Nursing and lead author of the family caregiver ENABLE Trial outcomes. “This means palliative care is mistakenly associated solely with end-of-life care. This is unfortunate. Our research shows that integration of palliative care earlier in the cancer trajectory benefits both patients and their family caregivers.”

“These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”

The investigators say that family caregivers who receive this support and education have greater capacity and skills to deliver high-quality support to patients. Likewise, providing patients with palliative care early eases the burden on families, who deliver the majority of care and psychosocial support in the home. 

“Anyone who has been through cancer with a family member can attest to the physical, psychological and existential burden it places on both parties,” Dionne-Odom said. “Receiving this extra layer of support early and at the same time as curative medical treatments is vital for helping patients and their family caregivers develop the coping and other skills needed for the ups and downs of their journey.”

Bakitas says two other shifts in the view of palliative care also are needed.

“Reimbursement mechanisms need to incentivize this care to be offered regardless of six-month prognosis, which is the current hospice-benefit requirement,” Bakitas said. “Also, increased clinician education is needed to train both specialists and general practitioners in palliative care.”

Both researchers say mechanisms still need to be identified that explain the effects of early palliative care, and they are looking at the impact of depression and biological mechanisms that might contribute to this explanation.

Bakitas recently was awarded a five-year, $3.5 million National Institute of Nursing Research R01 grant to study whether palliative care provided to advanced heart-failure patients while they are well results in a better quality of life, improved mood, and less symptom distress/burden for patients and/or caregivers when compared to usual heart-failure care. It will test this similar intervention using materials and an approach adapted from the ENABLE cancer intervention.

A possible novel therapy for a rare but potentially fatal blood disorder
A possible novel therapy for a rare but potentially fatal blood disorder
Similar to the ancient Greek legend of the Trojan horse, platelets in a transgenic mouse deliver a life-saving enzyme.

xinglong zhengIn a city of 1 million, about 10 to 15 patients a year will come to the emergency department with indistinct complaints that hide a potentially fatal blood disease.

“They usually come in the middle of the night, and the symptoms can be very nonspecific,” said X. Long Zheng, M.D., Ph.D., professor and division director of Laboratory Medicine in the Department of Pathology, University of Alabama at Birmingham School of Medicine. “Headache, blurred vision, malaise and abdominal pain. If misdiagnosed, they can die in one to two days.”

This syndrome — acquired thrombotic thrombocytopenic purpura, or TTP — produces blood clots in small arterioles throughout the body, particularly in the brain, heart, pancreas and kidneys. The most effective treatment thus far is daily plasma exchange, with replacement of all or one and a half times the body’s entire blood volume. Such treatment costs nearly $10,000 a day and may need to be continued for weeks or, in some patients, months.

Zheng and colleagues have now developed a potential novel way to treat acquired TTP. Their approach not only could slash the amount of plasma transfusion needed for TTP patients, but also could become a new emergency therapy for strokes, heart attacks, malignant malaria and pre-eclampsia. All are associated with relative deficiency of plasma ADAMTS13 activity. The work, now a proof-of-concept in a mouse TTP model, has been published online this week in the journal Blood.

TTP is an autoimmune disorder — people produce an autoantibody that inactivates an enzyme called ADAMTS13. Of note, Zheng was the first scientist to clone ADAMTS13. That enzyme normally acts to cleave von Willebrand factor, a large protein involved in blood clotting. The loss of ADAMTS13 activity due to autoantibody in TTP patients allows formation of the destructive microvascular clots in many important organ tissues.

Zheng had an idea of how treat TTP: “Hide the enzyme inside cells where the antibody can’t see it.”

His cells of choice were platelets, tiny blood cells a fifth the diameter of a red blood cell.

The normal function of a platelet is to stop bleeding from blood vessels. “When the platelet sticks to the injured site, it gets activated, changes its shape and releases its contents,” said Zheng. “It’s like a mini-bomb.”

Zheng reasoned that, if he could fill the platelets with ADAMTS13, the platelets would then carry the enzyme right to the place it was most needed to dissolve the TTP clots.

For the proof-of-concept, his research group developed transgenic mice that expressed functional recombinant human ADAMTS13 (rADAMTS13) in mouse platelets.

The group then showed that:

  • The platelets with the human rADAMTS13 had normal agglutination and aggregation.
  • The platelets released rADAMTS13 upon stimulation with clot inducers.
  • The mice with rADAMTS13 inside platelets were significantly protected in a vascular injury model of thrombus formation.
  • The same mice were protected against bacterial toxin or recombinant von Willebrand factor-induced TTP due to hereditary deficiency of ADAMTS13, a genetic disease where an offspring makes little or no ADAMTS13 (although hereditary TTP is much rarer than acquired TTP).
  • These mice were also protected against antibody-mediated TTP after being challenged by recombinant von Willebrand factor.

All of these findings of the study, they conclude, “suggest that platelets may be ideal carriers for antithrombic ADAMTS13, allowing its release at high concentrations at the site of thrombus formation without being inactivated by the potential circulating anti-ADAMTS13 inhibitors.”

Of course, genetic engineering or biochemical approaches would not be used to apply this proof-of-concept to human TTP patients. Zheng says one approach will be to learn how to pack ADAMTS13 inside the human platelets during the time that bags of donated blood sit at room temperature for three days as they are tested for multiple infectious disease markers. These packed platelets would then be tested to learn how many ADAMTS13-loaded platelets need to be transfused to get anti-blood clot and anti-TTP effects in patients with acquired TTP. Platelets do not have nuclei, and they lack the blood type ABO antigen markers found on red blood cells.

The co-authors of the paper, “Platelet-delivered ADAMTS13 inhibits arterial thrombosis and prevents murine models of thrombotic thrombocytopenic purpura,” include Drs. Brandy Pickens, Yingying Mao, Dengju Li, Don Siegel and Douglas Cines from the departments of Pathology and Laboratory Medicine, University of Pennsylvania; and Dr. Mortimer Poncz from the Division of Hematology, Children’s Hospital of Philadelphia.

Zheng has recently joined faculty at the University of Alabama at Birmingham. He has been an NIH-sponsored investigator of TTP since 2003.

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