Program Co-Directors:

Doug Ayers, Ph.D.
dayers@uab.edu

Lisa Schwiebert, Ph.D.
lschwieb@uab.edu

The mission of the Business Certificate Program in Life Sciences Entrepreneurship is three-fold:

  • To provide knowledge in the areas of business and entrepreneurship to UAB graduate students, Postdocs, and faculty
  • To further cross-institutional collaborations among UAB schools
  • To promote interactions between UAB and the Birmingham business community

The program includes three required courses in Business Planning (MBA 673), Understanding the Biotech Industry (MBA 681), and Innovation (MBA 690).  Each of these courses is 3 credit hours. There are no pre-requisites and these courses may be taken in any order.

Current UAB graduate students may register directly.  If you are not a current graduate student, you will need to apply to the UAB Graduate School as a non-degree seeking student. Non-degree seeking students will need to contact Christy Manning at (205) 934-8815 or cmanning@uab.edu for more information.
 

Postdocs in UAB News

  • New role for immature brain neurons in the dentate gyrus identified

    Researchers have proposed a model that resolves a seeming paradox in one of the most intriguing areas of the brain, exploring how immature granule cells in the dentate gyrus appear able to enhance pattern separation due to lesser synaptic connectivity than mature cells.

    University of Alabama at Birmingham researchers have proposed a model that resolves a seeming paradox in one of the most intriguing areas of the brain — the dentate gyrus.

    This region helps form memories such as where you parked your car, and it also is one of only two areas of the brain that continuously produces new nerve cells throughout life.

    “So the big question,” said Linda Overstreet-Wadiche, Ph.D., associate professor in the UAB Department of Neurobiology, “is why does this happen in this brain region? Entirely new neurons are being made. What is their role?”

    In a paper published in Nature Communications on April 20, Overstreet-Wadiche and colleagues at UAB; the University of Perugia, Italy; Sandia National Laboratories, Albuquerque, New Mexico; and Duke University School of Medicine; present data and a simple statistical network model that describe an unanticipated property of newly formed, immature neurons in the dentate gyrus.

    These immature granule cell neurons are thought to increase pattern discrimination, even though they are a small proportion of the granule cells in the dentate gyrus. But it is not clear how they contribute.

    This work is one small step — along with other steps taken in a multitude of labs worldwide — towards cracking the neural code, one of the great biological challenges in research. As Eric Kandel and co-authors write in Principles of Neural Science, “The ultimate goal of neural science is to understand how the flow of electrical signals through neural circuits gives rise to the mind — to how we perceive, act, think, learn and remember.”

    Newly formed granule cells can take six-to-eight weeks to mature in adult mice. Researchers wondered if the immature cells had properties that made them different. More than 10 years ago, researchers found one difference — the cells showed high excitability, meaning that even small electrical pulses made the immature cells fire their own electrical spikes. Thus they were seen as “highly excitable young neurons,” as described by Alejandro Schinder and others in the field.

    But this created a paradox. Under the neural coding hypothesis, high excitability should degrade the ability of the dentate gyrus — an important processing center in the brain — to perceive the small differences in input patterns that are crucial in memory, to know your spatial location or the location of your car.

    “The dentate gyrus is very sensitive to pattern differences,” Overstreet-Wadiche said. “It takes an input and accentuates the differences. This is called pattern separation.”

    The dentate gyrus receives input from the entorhinal cortex, a part of the brain that processes sensory and spatial input from other regions of the brain. The dentate gyrus then sends output to the hippocampus, which helps form short- and long-term memories and helps you navigate your environment.

    In their mouse brain slice experiments, Overstreet-Wadiche and colleagues did not directly stimulate the immature granule cells. They instead stimulated neurons of the entorhinal cortex.

    “We tried to mimic a more physiological situation by stimulating the upstream neurons far away from the granule cells,” she said.

    Use of this weaker and more diffuse stimulation revealed a new, previously underappreciated role for the immature dentate gyrus granule cells. Since these cells have fewer synaptic connections with the entorhinal cortex cells, as compared with mature granule cells, this lower connectivity meant that a lower signaling drive reached the immature granule cells when stimulation was applied at the entorhinal cortex.

    The experiments by Overstreet-Wadiche and colleagues show that this low excitatory drive make the immature granule cells less — not more — likely to fire than mature granule cells. Less firing is known in computational neuroscience as sparse coding, which allows finer discrimination among many different patterns.

    “This is potentially a way that immature granule cells can enhance pattern separation,” Overstreet-Wadiche said. “Because the immature cells have fewer synapses, they can be more selective.”

    “It’s almost like they are a different neuron for a little while that is more excitable but also potentially more selective.”

    Seven years ago, paper coauthor James Aimone, Ph.D., of Sandia National Laboratories, had developed a realistic network model for the immature granule cells, a model that incorporated their high intrinsic excitability. When he ran that model, the immature cells degraded, rather than improved, overall dentate gyrus pattern separation. For the current Overstreet-Wadiche paper, Aimone revised a simpler model incorporating the new findings of his colleagues. This time, the statistical network model showed a more complex result — immature granule cells with high excitability and low connectivity were able to broaden the range of input levels from the entorhinal cortex that could still create well-separated output representations.

    In other words, the balance between low synaptic connectivity and high intrinsic excitability could enhance the capabilities of the network even with very few immature cells.

    “The main idea is that as the cells develop, they have a different function,” Overstreet-Wadiche said. “It’s almost like they are a different neuron for a little while that is more excitable but also potentially more selective.”

    The proposed role of the immature granule cells by Overstreet-Wadiche and colleagues meshes with prior experiments by other researchers who found that precise removal of immature granule cells of a rodent, using genetic manipulations, creates difficulty in distinguishing small differences in contexts of sensory cues. Thus, removal of this small number of cells degrades pattern separation.

    The first author of the paper, “Low excitatory innervation balances high intrinsic excitability of immature dentate neurons,” Cristina Dieni, Ph.D., was a postdoctoral fellow at UAB and now has an independent position at University of Perugia, Italy. Coauthors include Jacques I. Wadiche, UAB Department of Neurobiology and Evelyn McKnight Brain Institute; Roberto Panichi, University of Perugia, Italy; James B. Aimone, Sandia National Laboratories, Albuquerque, New Mexico; and Chay T. Kuo, Duke University School of Medicine. Corresponding author is Overstreet-Wadiche.

    This work was supported by NIH grants NS064025, NS065920, NS047466, MH105416 and NS078192, and by the Laboratory Directed Research and Development program, Sandia National Laboratories. Sandia National Laboratories is a multi-program laboratory managed and operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Corporation, for the US Department of Energy’s National Nuclear Security Administration under contract DE-AC04-94AL85000.

  • Palliative care makes every moment count
    Palliative care helps patients get the most out of life, whether they’re newly diagnosed, a survivor, or nearing the end of their journey. UAB’s palliative care pioneers provide a fresh look at the fast-growing specialty and its emphasis on listening, choices, patient goals, and quality of life.
    Illustrations by Ernie Eldredge

    What do you want out of life?

    For someone facing a serious, chronic illness, the answers to that question take on a sharp focus. A patient with heart disease might want enough energy to walk around the neighborhood. A cancer survivor may want to feel like herself again after rounds of chemotherapy. Others might have a goal of seeing their children get married—or perhaps to get married themselves.

    Helping patients get the most out of life is the aim of palliative care—which could surprise some people who associate the specialty with hospice, or care delivered in the final days and hours. Palliative care services do indeed benefit people nearing the end of their journey, but the field has become much broader over time. Many patients with a life-threatening disease now start receiving palliative care early—sometimes soon after diagnosis—to support them throughout their fight. In fact, palliative care now ranks among the fastest growing medical specialties—67 percent of U.S. hospitals with 50 or more beds offer it, according to a 2015 report from the Center to Advance Palliative Care (CAPC)—in part because patients, families, and physicians like its emphasis on personalized treatment goals and quality of life.

    Care + comfort

    Perhaps the best way to understand the value of palliative care is to recall a time—not long ago—when such care was scarce. Marie Bakitas, D.N.Sc., remembers it well. Earlier in her career, before becoming the Marie L. O’Koren Endowed Chair and professor in the UAB School of Nursing and associate director of the UAB Center for Palliative and Supportive Care (CPSC), Bakitas wondered about the “invisible” patients—the ones who weren’t responding to pioneering cancer treatments. They didn’t have a lot of resources or support, she noted.Marie Bakitas and Rodney Tucker lead the UAB center providing an extra layer of support for patients dealing with serious illnesses.

    Likewise, J. Nicholas Dionne-Odom, Ph.D., a School of Nursing postdoctoral fellow who worked as an intensive-care unit nurse for 10 years, saw patients and families navigating a traumatic “alien environment” of life-sustaining machines and uncomfortable procedures. “They often were dumbstruck,” he explains. “It was not how they imagined the end of their lives.”

    The “extra layer of support” that palliative care provides can make all the difference, both physically and emotionally, Bakitas says. Teams of specialists focus on the patient’s comfort, managing symptoms such as pain, breathing issues, nausea, vomiting, and sleeping problems, to name a few examples, along with depression, anxiety, and spiritual issues. They also help patients and families make health-care decisions and plan for the future.

    What these teams don’t do is replace a patient’s primary- or specialty-care physicians. Many patients concurrently receive treatments geared toward cure or remission, and the palliative care team works in tandem with their doctors. That’s the case with many cancer patients, says Rodney Tucker, M.D., director of the UAB CPSC. The same goes for “a heart-failure patient struggling earlier in the disease process, or a patient and family early in the diagnosis of Alzheimer’s disease who need a discussion about advance care planning and what to anticipate,” he adds. “Any patient with an illness that is life-threatening or life-limiting — one that causes severe decreases in quality of life — could benefit from palliative care.” Age, disease, and stage of disease progression do not matter.

    “We’ve shown that people who engage in palliative care early and concurrently have improved survival rates,” Tucker says. “That’s the opposite of what many people think — that if I’m acknowledging my serious illness, then I’m giving up hope. When people are aware of all their choices, then they often select options that improve the quality of their lives when the quantity of their lives is limited.”

    Symptoms, choices and goals

    Here’s an example of one of those choices: Let’s say you’re a cancer patient with a normal life expectancy, but you’re dealing with the side effects from treatment. Is the best solution a medication with its own powerful side effects such as confusion or drowsiness? Or do you pursue other forms of symptom management with less impact on your day-to-day life?

    Specialist teams led by Ashley Nichols, left, and Elizabeth Kvale design palliative care plans to meet patient and family goals.

    Elizabeth Kvale, M.D., might advise you to choose the latter. She directs the UAB Supportive Care and Survivorship Clinic, located at The Kirklin Clinic of UAB Hospital. UAB was among the first palliative care programs to establish an outpatient clinic, around 2000, and it’s where Kvale and her team help patients who are living with cancer, advanced heart disease, lung disease, or other serious conditions. Some of those patients still receive medical treatment for their chronic diseases, while others have completed it. Kvale and her colleagues help all of them manage symptoms. She compares the clinic to “a good corner man in a boxing match, who can keep patients patched up enough to stay in the fight if they want to do that.”

    A few blocks away, another team, led by Ashley Nichols, M.D., staffs UAB Hospital’s 12-bed Palliative and Comfort Care Unit. Each room resembles a hotel suite, with comfortable leather couches, warm lighting, and wood accents—and the comparison is appropriate, Nichols says, because it is a “transitional unit.” Here, critically ill patients and their families have an option beyond the ICU while they are in the hospital, and for many of them, the next stop is their own home. “That’s where so many patients want to be,” says Nichols, a School of Medicine assistant professor. “So we work to control their symptoms, and we work with families and community hospice partners to develop a care plan to get them back home.”

    Beyond the unit, Nichols and her group visit patients with every kind of disease throughout UAB Hospital, provide care at the Veterans Affairs Medical Center and Children’s of Alabama, and coordinate continued care with community hospice partners; they even do a few home visits. Typically, the team works with physicians on late-stage care, “but we’re also consulted more upstream—earlier in the disease process—when teams recognize an uncontrolled symptom burden, such as shortness of breath from chronic obstructive pulmonary disease, pain from a newly diagnosed cancer, or depression and anxiety associated with any chronic illness,” Nichols says. “If a symptom bothers patients, then it bothers us. We can partner with them and their physicians early and help manage symptoms throughout the course of the disease, as well as talk about goals for the patient’s care.”

    Those goals are the key to quality palliative care, no matter the setting. What do patients want to accomplish—today, tomorrow, and in the rest of their lives? What kind of care will help them achieve their aims? Helping patients weigh the benefits of medical interventions against the potential costs to their quality of life, not to mention their pocketbook, is “the crux of what we do,” says Kvale, an associate professor in the School of Medicine. “Our objective is to align our care plan with patient and family goals. We also want to provide a space where it is OK for them to begin exploring other options, such as not seeking further invasive treatments.”

    Strength in numbers

    A hospital is not the easiest place to perform a full-immersion baptism, but UAB Pastoral Care chaplains have made it happen, thanks to an arrangement with UAB’s therapy pool. They also have officiated marriages for patients, complete with music and wedding cake; nurses helped one bride with a dress and makeup.

    Mostly, though, they simply talk with patients about their sources of strength and the big questions that arise in tough times, sometimes without bringing up religion at all.

    The chaplains are part of the interdisciplinary teams that staff the Palliative and Comfort  Care Unit and the Supportive Care and Survivorship Clinic. Both groups bring together a variety of specialists who can help patients relax physically and cope mentally: physicians, nurses, psychologists, social workers, dieticians, physical therapists, music therapists, and even massage and pet therapists, in addition to spiritual care. In meetings, each professional provides a different perspective on what each patient needs; the result is a comprehensive, holistic, seamless care plan, Nichols says.

    Teams also support families and caregivers. “Most of our patients live in the community and try to manage their illnesses with the help of a caregiver, so if we aren’t helping them engage with what’s going on with the patient, then the system is likely to fail,” Kvale says. “It’s a place where palliative care can have a big impact.”

    A way forward

    Listening may be the teams’ most powerful tool. When patients and families share their stories, they reveal much about their symptoms and quality of life—but also their joys, fears, loves, regrets, relationships, and unfinished business.

    Diane Tucker, left, and Kay Knowlton encourage patients and families to talk about grief, fear and the future.

    “We listen with no agenda; we’re not trying to diagnose anything or resolve relationship issues,” says counselor Kay Knowlton, Ph.D. The overriding emotion is grief, she adds—grief over the end of life, or grief over life changes caused by illness. For example, a patient in the Supportive Care and Survivorship Clinic whose cancer is in remission might not look sick, but chemotherapy and radiation may have affected her sight, hearing, cognitive function, and ability to return to work.

    “She’s coping with losses as well,” says Diane Tucker, Ph.D., a UAB psychology professor who also counsels palliative care patients. “She can’t go back to where she was before treatment.”

    Diane Tucker and Knowlton help patients and families adjust to their new normal by talking with them about the future—how to move forward and accomplish what they consider important—without discounting the sadness, worry, or anger they might be experiencing. Tucker notes that suffering and pain are partly psychological. Helping patients handle their tension and fear can bring some relief.

    Often, the psychologists help patients leave a legacy for their loved ones. Patients might write letters to their children or grandchildren, to be read when they are graduating from high school, getting married, or marking other milestones. Patients and families also can use the hospital unit’s art station to create a treasured memento.

    Knowlton recalls helping one nine-year-old girl make handprints with her ill grandmother. The big and small handprints touched at the thumbs. “It didn’t mean that the girl wasn’t going to cry anymore, but it was a connection she needed because her grandma was leaving,” Knowlton says.

    Likewise, the marriage ceremonies that the chaplains have performed create legacies for family members. Sometimes it means that the survivors can receive benefits. But these special moments also become pieces of family history that they can cherish for the rest of their lives.

    Long-distance learning

    Although palliative care has made great strides in recent years, millions more patients stand to benefit from it—if they can access it. The specialty is scarce or nonexistent in smaller hospitals, rural areas, and minority and underserved communities, says Bakitas. Alabama traditionally has ranked among the states with the lowest access, with less than one third of hospitals offering palliative care, according to the 2015 CAPC report. And there are a host of reasons why: lack of palliative care knowledge among health providers, socioeconomic factors, geographic distance, and transportation issues, among others.

    Bakitas, along with Dionne-Odom, is bridging those gaps via telehealth—teaching palliative care principles to patients over the phone. Health coaches “show patients how to build upon the strengths of their personal, family, and community resources,” Bakitas says. They also talk about problem-solving and decision-making, self-care, early symptom management, communicating health concerns to clinicians, and emotional and spiritual topics. “We help people think about their illness in context,” she explains. “The illness is not who they are; it’s only a piece of their lives.”

    Dionne-Odom develops telehealth programs for family caregivers as well as patients newly diagnosed with advanced illness. Caregivers often experience levels of stress and anxiety equal to—and sometimes greater than—those of patients, he notes. Talking with a health coach offers an outlet to express what they’re experiencing and to learn skills and coping abilities.

    In fact, a recent study led by Dionne-Odom was the first to show that early palliative care benefits caregivers as well as patients. For caregivers of patients with advanced cancer living in rural areas, depression scores improved when those caregivers received palliative care via telehealth within a month after diagnosis, as opposed to those whose patients received care four months later. For patients in the study, one-year survival improved by 15 percent.

    Now, with support from the National Palliative Care Research Center, Dionne-Odom is laying the groundwork for a new intervention to coach family caregivers at diagnosis, through the course of disease, and into bereavement. He hopes to implement the initiative in rural areas of Alabama and the Deep South.

    Bakitas also is expanding her investigations with a $3.5-million National Institute of Nursing Research grant to study whether early palliative care, delivered by phone, can improve quality of life, mood, and symptom burden for advanced heart-failure patients and their caregivers. The American Cancer Society also awarded her a grant to study the impact of a phone-based intervention for veterans, minorities, and rural patients with advanced cancer.

    Jessica Merlin and J. Nicholas Dionne-Odom are adapting palliative care for rural areas and diseases such as HIV.

    What patients want

    UAB researchers also are expanding palliative care’s boundaries by adapting it for other serious diseases. Few specialists had studied the intricacies of chronic pain in patients with HIV before Jessica Merlin, M.D., M.B.A., began her work. “It’s not clear why there’s a lot of chronic pain with HIV,” says Merlin, assistant professor and director of the HIV Pain/Palliative Care Clinic at UAB’s 1917 Clinic. “Does something with HIV predispose patients to pain?” To complicate matters, some patients might experience chronic pain not caused by HIV, such as migraines or arthritis, and current medications aren’t entirely effective and may carry risks, she adds.

    Now Merlin is developing an intervention—supported by a National Institutes of Health grant—that relies on behavioral therapy instead. “It’s unlikely that a pill can take away chronic pain, so we need to help patients put their pain in the background and themselves in the foreground,” Merlin explains. She envisions a program in which patients learn pain self-management skills from a trained provider.

    “This is practical,” Merlin says. Medical research suggests that “when patients come to physicians and other providers, their highest priorities are treating pain and other symptoms.”

    Lessons at the bedside

    To ensure that health professionals understand quality-of-life issues, the UAB CPSC has a robust educational program. UAB students and residents in medicine, nursing, clinical psychology, and social work rotate through or intern in the clinic and hospital unit. For many, “this may be the first encounter with a patient who’s dying,” Nichols says. And that leads to important early lessons about discussing difficult end-of-life decisions with patients, handling anger and sadness from families, and responding personally to the loss of a patient. It also influences how future professionals look at life and death, Nichols adds. “Death is not a failure, but an opportunity to support patients and families.”

    Physicians, nurses, and others seeking advanced training can join UAB’s specialized fellowship program or its clinical training academy, which has attracted professionals from as far away as Australia to observe UAB palliative experts at work. In addition, “we have trained 85 health-care institutions across the country and one in Korea about building business plans around palliative care,” Rodney Tucker says.

    "We've shown that people who engage in palliative care early and concurrently have improved survival rates"

    Reaching further

    Palliative care will continue to grow and become more common throughout health care, say UAB’s experts. The field’s focus on patients and their goals offers a template for personalized medicine. And demand for it will rise as health care shifts toward “managing disease crises at home quickly and efficiently so that patients don’t need to come to the hospital,” Nichols says.

    “We must learn better ways to partner with care organizations closer to the patient—including those that may not be considered palliative care, such as home-care organizations and skilled nursing facilities,” Rodney Tucker says. This year, the CPSC will establish the Southeast Institute for Innovation in Palliative and Supportive Care, which will educate health workers in communities throughout the region and conduct research to better understand the needs of seriously ill patients and families. Some of those initiatives may build on UAB’s pioneering work in telehealth and the training of lay navigators—people in community settings who can help patients make sense of the health-care system and their options.

    While the new institute will give UAB a greater voice in the national conversation about palliative care, the specialists on UAB’s care teams feel privileged to help Alabama’s mothers and fathers, sons and daughters, and their families and friends maximize their lives when facing tough situations and choices.

    “The truth is that none of us know how much time we have left,” Knowlton notes. “So what is today about? How can we live today in the best way possible?”

    Pioneering a new kind of care

    Some of the seeds for palliative care’s rapid growth were planted in the 1990s by a team led by UAB psychiatrist John Shuster, nurse scientist Pam Fordham, and medical oncologist Amos Bailey. Their partnership brought together the UAB schools of Medicine and Nursing and Cooper Green Hospital to promote clinical care, education, and research in the emerging field. The group soon established some of the nation’s earliest fellowship programs for physicians and training tracks for nurse practitioners.

    Ten years ago, the UAB Center for Palliative and Supportive Care opened two clinical units, at UAB Hospital and the Birmingham Veterans Affairs Medical Center, within six months. At that time, when many major cities across the country barely had one inpatient palliative care facility, Birmingham had three, counting Cooper Green’s unit.

    Nationally, UAB is one of only 11 Palliative Care Leadership Centers, which train and mentor other institutions launching their own clinical programs, and was among the first nursing education programs in palliative care. UAB also is a founding member of the national Palliative Care Research Cooperative Group.

  • Moore selected for competitive American Council of Learned Societies Fellowship
    The fellowship will help further the completion of the first study, bilingual edition of a centuries old legal case.

    John K. Moore Jr., Ph.D., has been awarded a fellowship from the American Council of Learned Societies. Moore is an associate professor of Spanish in the UAB College of Arts and Sciences Department of Foreign Languages and Literatures.

    The $45,000 award is to further the completion of Moore’s bilingual edition and study of “His Majesty’s Prosecutor v. José Soller, Mulatto Pilgrim, for Impersonating a Priest and Other Crimes,” a previously unedited and unpublished legal case from late 17th-century Spain. José Soller was traveling as a pilgrim from Lisbon, Portugal, to Santiago de Compostela, Spain, and had intended to continue from there to Rome, Italy, when he was apprehended in Ourense, Spain, in 1693 for impersonating a priest. This body of work will be the first study, edition and translation of the case.

    Moore is one of 70 fellows selected from more than 1,100 applicants. Fellows and grantees are selected by a committee of scholars. Moore’s project was received well by the review committee.

    “The discovery of this fascinating trial record of a mulatto who was prosecuted in Spain in 1693 for impersonating a priest while embarked on a pilgrimage from Lisbon to Santiago de Compostela is a rare find,” the committee noted. “The trial record and supporting documents provide fantastic windows into the legal status and treatment of black slaves in Spain during this period and stand in contrast to that in the New World. The details of black experience and the breach of conventional social structures (encroachment on the priesthood and on the very conception of holiness and piety) are intriguing; there does not seem to be anything like this elsewhere. This work will be of broad interest.”

    The ACLS is a private, nonprofit union of 73 national scholarly organizations devoted to the advancement of humanistic studies in all fields of learning in the humanities and the social sciences and the maintenance and strengthening of relations among the national societies devoted to such studies. It is the leading private institution supporting scholars in the humanities and related social sciences at the doctoral and postdoctoral levels. The ACLS's contributing institutions include The Andrew W. Mellon Foundation, the Ford Foundation, the Rockefeller Foundation, the National Endowment for the Humanities, and the William and Flora Hewlett Foundation.

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UAB Research News

  • Parkinson’s disease pathogenesis is reduced in a rat model using a cell-signaling inhibitor drug
    Results show that JAK/STAT pathway inhibitors may be a new class of therapeutic treatments for patients with Parkinson’s disease. Acting by reducing inflammation, they prevent neurodegeneration in animal models and may be an important new approach to slow progression of the disease.

    Etty “Tika” BenvenisteUniversity of Alabama at Birmingham researchers report the first documentation that suppressing a key cell-signaling pathway in a rat model of Parkinson’s disease reduces pathogenesis. Oral administration of AZD1480 — one of the JAK/STAT pathway inhibitors generally known as Jakinibs — lessened the destructive inflammation and nerve cell degradation in the area of the brain affected by Parkinson’s.

    At present, there are no therapies available to patients to prevent progression of Parkinson’s disease, the chronic neurodegenerative movement disorder marked by profound loss of dopamine-producing neurons in the brain.

    “We believe Jakinibs may become a viable therapeutic option for Parkinson’s disease patients,” said Etty “Tika” Benveniste, Ph.D., professor in the Department of Cell, Developmental and Integrative Biology and lead author of a paper published May 4 in The Journal of Neuroscience. “They are already being studied for other conditions, are orally bioavailable, seem to be well-tolerated, and do not promote troublesome immunosuppression. Furthermore, there may also be other ways of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative disease.”

    A variety of Jakinibs are in Phase I, II or III clinical trials for several other diseases. The current UAB study, funded by the Michael J. Fox Foundation for Parkinson Research and the National Institutes of Health, is the first to show that disrupting the JAK/STAT pathway prevents the neuroinflammation and neurodegradation specific to Parkinson’s disease.

    “This is a very important advance,” said David Standaert, M.D., Ph.D., professor and chair of the UAB Department of Neurology and a collaborator on the project. “It shows that anti-inflammatory strategies have real potential. The next steps will be to validate some of the inflammatory changes seen in the animals in patients with Parkinson’s disease, which in turn will enable planning of clinical studies of anti-inflammatory therapies in patients with Parkinson’s.”

    “This is a very important advance. It shows that anti-inflammatory strategies have real potential. The next steps will be to validate some of the inflammatory changes seen in the animals in patients with Parkinson’s disease, which in turn will enable planning of clinical studies of anti-inflammatory therapies in patients with Parkinson’s.” — David Standaert, M.D., Ph.D.
    Benveniste and Standaert are part of an interdisciplinary UAB team focusing on neuroinflammatory mechanisms in Parkinson’s disease. The group — co-led by Benveniste, Standaert and Andrew West, Ph.D., associate professor of neurology — seeks to understand how the body’s immune system contributes to the pathology seen in the brains of Parkinson’s disease patients and to the development and progression of the disease. Only recently have researchers begun to suspect an important role for inflammation in the disease, and this is still largely uncharted territory.

    For the current paper, UAB researchers, led by Hongwei Qin, Ph.D., associate professor of cell, developmental and integrative biology, either challenged rat immune cells in vitro with aggregated human α-synuclein, or induced overexpression of α-synuclein carried by a virus vector in brains of rats. Untreated, this in vivo model leads to neuroinflammation in the brain and degradation of dopamine-producing neurons in the substantia nigra, the portion of the midbrain marked by cell death in Parkinson’s patients. Accumulation of α-synuclein in the brains of patients is a core feature of Parkinson’s disease, and this leads to the activation of the brain immune cells called microglia, the production of inflammatory signaling chemicals, and ultimately, neurodegradation.

    In vitro and in vivo experiments showed AZD1480 inhibited JAK/STAT activation and downstream gene induction after a challenge by α-synuclein. The genes that are induced by α-synuclein, but not induced in the presence of α-synuclein and AZD1480, are associated with the proinflammatory phenotype. The inhibition by AZD1480 dampened both innate and adaptive immune responses.

    Altogether, the researchers say, the results show the potential of Jakinibs to protect against the degradation of dopamine-producing neurons.

    Details

    For the in vivo neuroinflammation experiments, α-synuclein overexpression was induced, and two weeks later rats were given AZD1480 by oral gavage for 14 days. Then the researchers analyzed the inflammatory response in the substantia nigra of the midbrain for AZD1480-treated and -untreated animals. AZD1480 prevented the increased numbers of microglia and macrophages seen after α-synuclein overexpression. AZD1480 also prevented inflammatory activation of the microglia, as measured by Iba1-positive cells, and it prevented upregulation of genes for the proinflammatory markers TNF-α, iNOS, IL-6 and CCL2.

    AZD1480 also prevented neurodegradation. For the in vivo neurodegradation experiments, α-synuclein overexpression was induced, and four weeks later — at the peak of neuroinflammation — rats were given a four-week treatment of AZD1480 oral gavage. At 12 weeks, the brains were analyzed for nigral neurons of the substantia nigra. Benveniste and colleagues found that overexpression of α-synuclein caused a 50 percent loss of nigral neurons at three months. But when the α-synuclein rats were also treated with AZD1480, that loss was prevented, and the numbers of nigral cells were similar to those of the controls.

    In Parkinson’s disease, chronic inflammation in the brain makes the blood-brain barrier more permeable, allowing immune system T-cells to infiltrate into the brain from the bloodstream, potentially adding to neuroinflammation. In the rat model, α-synuclein overexpression increased the infiltration of CD4+ T-helper cells and induced activation of the STAT3 signaling protein. AZD1480 treatment inhibited both of these immune responses. AZD1480 also inhibited induction of two genes for proinflammatory markers, CIITA and MHC Class II.

    The UAB researchers further found that α-synuclein overexpression significantly upregulated 186 genes in the midbrains of rats, while AZD1480 treatment of α-synuclein-overexpression rats inhibited the expression levels of 59 genes, the majority being genes that were induced by α-synuclein. Genes induced by α-synuclein overexpression include many that are implicated in cell signaling, inflammatory and neurological diseases, and antigen presentation (a step in the adaptive immune response).

    Besides Benveniste, Qin and Standaert, authors of the paper, “Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration,” are Jessica A. Buckley, Yudong Liu, Thomas H. Fox III, Gordon P. Meares, Hao Yu and Zhaoqi Yan, all of the UAB Department of Cell, Developmental and Integrative Biology; Xinru Li and Ashley S. Harms, UAB Department of Neurology; and Yufeng Li, UAB Department of Medicine.

    At UAB, Benveniste holds the Charlene A. Jones Endowed Chair in Neuroimmunology, and Standaert holds the John N. Whitaker Endowed Chair in Neurology. West holds the John A. and Ruth R. Jurenko Endowed Professorship in Neurology.

    Research support came from the M.J. Fox Foundation, and from NIH grants RO1 NS57563-05, P20 NS095230, P30 AR48311, P30 NS47466, P30 CA13148 and P30 AI027767.

  • UAB driving simulator lab has national debut live on TODAY
    Cutting-edge technology and research brings national attention to UAB.
    Click the image above to play TODAY show segmentNBC’s TODAY show traveled to Birmingham to hear from UAB College of Arts and Sciences distracted driving expert Despina Stavrinos, Ph.D.

    On April 29, TODAY show correspondent Jeff Rossen reported live from UAB’s Translational Research for Injury Prevention Lab about the dangers of using social media and texting while driving.

    The TRIP Lab recently became home to the world’s first SUV simulator, made possible through donations from Honda Manufacturing of Alabama and the Alabama Department of Transportation.

    With the new simulator, UAB researchers hope to facilitate solutions and best practices in motor-vehicle-related safety and crash prevention, addressing the major public health problem of highway and traffic-related injuries and death. 

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