From Bench to Bedside with the Cerebrovascular Research Group
“A key component of our mission is to design therapeutic intervention strategies that are successful not only in the laboratory but also have real clinical potential,” says Louise D. McCullough, M.D., Ph.D., professor and chair of the department of Neurology at UTHealth Medical School and the new co-director of the Mischer Neuroscience Institute. “To ensure that these strategies are on track from their inception through application, the Group works closely with the neurology and neurosurgery services at Memorial Hermann-Texas Medical Center, as well as others at the Mischer Neuroscience Institute and The University of Texas Health Science Center at Houston. Targets identified in the lab are validated in clinical samples and translated back to animal models where manipulation in a controlled research environment is possible.”
Programs currently active include the evaluation of mechanisms underlying sex differences in stroke, understanding how social factors such as depression and social isolation impact stroke outcome, pregnancyassociated stroke risk and determining the impact of aging of the immune system on stroke-related cognitive decline.
In the future, Dr. McCullough will make education and mentoring a central theme within the Cerebrovascular Research Group by involving students at the high school, undergraduate, graduate, postgraduate, resident and fellowship level. “We want to give undergraduates opportunities to complete summer research projects or senior honors thesis projects,” she says. “Graduate and M.D./Ph.D. research opportunities also will be available, as will postdoctoral fellowships, resident research projects and opportunities for collaboration for developing faculty.”
The goal is to provide infrastructure that will benefit graduate students and faculty with an interest in translational science and animal models of neurological diseases, specifically in ischemic brain injury, neuroimmunology and aging. Group members want to provide an interdisciplinary environment and scientific and intellectual resources to researchers throughout the Texas Medical Center. “With the exceptionally strong clinical stroke program led by Dr. Sean Savitz, the translational science infrastructure and biorepositories already here at UTHealth and Memorial Hermann, we have a unique and unprecedented opportunity to make an impact on stroke care in the immediate future,” she says.
Dr. McCullough is principal investigator of five research studies funded by the National Institute of Neurological Disorders and Stroke (NINDS), including a $2.2 million study examining chromosomal and hormonal contributions to sex differences in ischemic stroke. “New experimental data has shown that brain cells die differently in males and females, and each sex responds differently to neuroprotective strategies,” she says.
“Because stroke is now the No. 1 cause of disability, new treatments are urgently needed.” She is also principal investigator in a NINDS-funded study of the neuroprotective potential of TGF-beta activated kinase inhibition in acute stroke. The study is testing promising therapies in a variety of animal models before moving them to clinical trials.
“New data from the bench has identified a novel signaling pathway involved in the response to stroke,” Dr. McCullough says. “We’re testing if inhibition of this pathway is protective in aging in the hope of improving stroke outcomes in older patients.”
Other studies led by the Cerebrovascular Research Group include an investigation of the hypothesis that microchimeric cells home to the site of injury as part of the immune response to stroke, and display a stem cell phenotype with potential to aid in repair, led by Dr. McCullough and funded by NINDS; the potential neuroprotective efficacy of a novel formulation of human inter-alpha inhibitors as a viable treatment for stroke, also led by Dr. McCullough and funded by NINDS; an investigation of the functional role of CaMK signaling in stroke, led by Jun Li, Ph.D., and funded by an R01 grant from the National Institutes of Health (NIH); a study of the effects of X chromosome-linked proteins on sexual dimorphism in ischemic stroke, led by Fudong Liu, M.D, with funding from the American Heart Association; and a study of how manipulation of the IRF5-IRF4 regulatory axis in microglia/infiltraging leukocytes may help limit ischemic injury and promote tissue repair after stroke, led by Dr. Liu and funded by an R01 grant from the NIH.
Dr. Liu was also recently awarded an R21 grant to examine sex differences in inflammation after neonatal stroke. Finally, the role of an emerging cytokine, macrophage migration inhibitory factor (MIF) levels in depression and post-stroke recovery, is being examined in animal and clinical samples, research led by Venugopal Reddy Venna, Ph.D., with funding from the American Heart Association.