Louise McCullough MD/PhD, Principal Investigator
Dr. Louise McCullough is an internationally known physician-scientist who has championed for the importance of the inclusion of females in preclinical research. Her laboratory focuses on the investigation of sex and age differences in inflammatory signaling in both the brain and peripheral tissues after stroke. A major area of recent work investigates the mechanisms by which social isolation increase mortality and impairs recovery after stroke, an effect also seen in humans. Social isolation alters the immune response to stroke during chronic recovery. Her lab is currently attempting to reduce age-related inflammation both in the brain and periphery to reduce brain injury using bone marrow replacement and manipulation of the microbiome. She is also developing a new model of multi-infarct dementia in aged animals. This preclinical work integrates with translational and clinical studies that examine the inflammatory response to stroke in patients. She is funded by the NIH (previously awarded the Javitz Award) and the NIA.
During my doctoral training, I explored potential therapeutic targets for the management of ischemic stroke. I found that the immunosuppressive agents, rapamycin and mycophenolate mofetil effectively ameliorated the brain damage in ischemic injury. The protection was a consequence of the reduction of inflammation and oxidative stress inducer by these agents. Besides investigating potential therapeutics for ischemic stroke, I have explored the contribution of peripheral immune cells in the process of aging as well as ischemic stroke. I found that with age, the spleen harbors more myeloid cells that then migrate to the site of injury and aggravate brain damage after ischemic stroke. Additionally, my other research project focuses on investigating the role of TGF-beta Activated Kinase inhibition in acute stroke. I am also investigating the role of GDF11 in aging and its effect on stroke outcomes in older animals, for which I was awarded an AHA Post-Doctoral Fellowship Grant.
Dr. Ganesh’s research team focus mainly on the role of gut physiology on brain diseases like stroke, hypertension, cerebral amyloid angiopathy, AD and other aging related diseases. The long-term goal of the research team is to elucidate the role of intestinal microbiome in interfering with intestinal epithelial homeostasis causing onset and activation of chronic inflammation with respect to neurodegenerative diseases associated with aging. Currently Dr. Ganesh’s lab research is focused on the “BRAIN-GUT Axis”. Investigating the interaction of the microbiome and their secretory products on modulating physiology of brain in diseases of age. We hope to identify the changes in mucosal modifications, including the immune response with respect to dysbiotic gut microbiome as possible biomarkers in predicting aging related diseases at an earlier stage.
Dr. Kim has interest in the role of reactive oxygen species after ischemia-reperfusion in stroke and signal transduction in cerebrovascular diseases. His current research project focuses on understanding of the molecular and cellular changes such as inflammation and new vessel formation in thalamus induced by primary cortical infarction. To address this question, Dr. Kim utilizes in-vivo animal stroke models with various knockout, transgenic and reporter mice, and in-vitro primary cell model system.
Dr. Lee’s Laboratory of Neuro-Mucosal Immunology explores (1) neuro-immune interactions, (2) host-microbe interactions, (3) inter-organ communication and (4) host metabolism. Specifically, these interdisciplinary studies include investigating the bidirectional communication between the brain, host mucosal tissues (e.g., gastrointestinal, respiratory and urogenital tracts) and metabolic tissues (e.g., liver and adipose tissues) in the context of age-related neurological diseases and psychosocial stress. The Lee Laboratory aims to interrogate the unknown mechanisms and target dysregulation in diseases with the goal of identifying novel therapeutic options by utilizing state-of-art techniques for metagenomics (e.g., microbiome), metabolomics and flow cytometry. Very recently, the Lee Laboratory has also established two experimental platforms within the laboratory for translational and innovative research: (1) patient induced pluripotent stem cells (iPSCs)-derived organoids and assembloids and (2) single-cell and spatial transcriptomics and related key instruments for single-cell RNA sequencing study.
Dr. Li’s lab aims to identify novel therapeutic approaches to reduce mortality and disability resulting from stroke. Dr. Li’s research currently is funded by the National Institutes of Health (NIH) to investigate the astrocytic and neuronal interaction in recovery after cerebral ischemia. The lab has been investigating axonal plasticity, neuronal and vascular regeneration, as well as brain functional recovery after cerebral ischemia. His team has extensive experience in vivo and in vitro stroke models, pharmacology, brain blood flow measurements, brain immune regulation, viral vector transduction, models for neurite plasticity studies and long-term brain functional recovery assessments.
Dr. Liu’s lab focuses on innate immune responses to cerebral ischemia, especially the regulation of microglia activation. He is utilizing genetic and pharmacological methods to manipulate microglia activation and post-stroke inflammation. Another research direction in this lab studies the mechanisms underlying sex differences in stroke; special animal models (Four Core Genotype, XY*) are generated to explore the chromosomal effects on stroke sensitivity in animals throughout the lifespan. His lab uses animal models of neonatal stroke to investigate sex and hormonal effects in the developing brains.
Dr. Manwani is a Stroke Neurologist whose clinical and basic science research program focuses on Cardio-embolic strokes (strokes caused by Atrial Fibrillation) and Cerebral Amyloid Angiopathy. A major expertise of the lab is in studies of the Heart-Brain Axis. Strokes caused by Atrial Fibrillation (an irregularly irregular heart rhythm) are associated with worse outcomes and have a mortality rate of up to 33%. Dr. Manwani uses telemetry monitoring, small animal ECHO and flow cytometry in aged mouse models to study the complex role of aging and gender on atrial inflammation, arrhythmogenesis, strokes and cognitive decline. Another major area of interest in the lab is Cerebral Amyloid Angiopathy (CAA) which leads to vascular dementia and intracranial hemorrhages. Current studies in the lab are focused on deciphering the role of fibrinolytic pathway in amyloid clearance from the cerebral vasculature using mouse models of CAA and animal behavioral testing.
The Major Goal of the lab is to elucidate pathways that can be targeted to:
- Prevent Ischemic strokes/ Vascular dementia from Atrial fibrillation &
- Prevent Hemorrhagic strokes/ Vascular dementia caused by CAA
Research in Dr. Sean P. Marrelli’s lab is focused mainly within the category of vascular physiology. Dr. Marrelli has elucidated the role of various ion channels in endothelial calcium regulation and membrane potential to promote vasodilation. He has developed methods to promote centrally-driven hypothermia in conscious mice by pharmacologically targeting warm-sensing (TRPV1) channels in the thermoregulatory system. Dr. Marrelli has expertise in intravital imaging, vivo tissue perfusion measurements, measures of reparative angiogenesis, isolated pressurized arteries, patch clamp electrophysiology, intracellular calcium measurements, thermoregulation and therapeutic hypothermia.
During aging, the human brain experiences multiple molecular changes that lead to brain dysfunction. Dr. Moruno’s research focuses on two main aspects of the aged brain biology. On one hand, the aged brain losses its capacity to remove damaged organelles and toxic compounds from cells by autophagy downregulation. On the other hand, in the aged brain cells that constitute the cerebral vasculature (endothelial cells) might enter in an irreversible proliferative-arrest state (senescence), which negatively affects cerebral blood flow and cerebrovascular architecture. Both reduced autophagy and senescence cells accumulation in the aged brain are associated to brain dysfunction and dementia. Identifying targets involved in these mechanisms will help to develop new therapeutic approaches to prevent, or at least mitigate, dementia.
The Ritzel lab is interested in the far reaching, bidirectional impact of brain injury on immunity, organ systems, and biological aging. Dr. Ritzel’s translational research program explores several interrelated themes, including (1) the role of immune cells in the pathogenesis of stroke and traumatic brain injury, (2) injury-induced immune dysfunction/senescence, and (3) neuro-immune interactions in health and disease (3). Specifically, his team is interested in elucidating the influencing factors and mechanisms underlying brain aging- and brain injury-related changes in leukocyte function that result in neurological impairment and functional decline. To investigate these questions, the Ritzel lab employs a variety of immunological tools and complementary techniques in neuroscience, such as transgenic models, flow cytometry, neurobehavioral testing, and in vivo manipulations. The Ritzel Lab is dedicated to the discovery and development of novel immunomodulatory therapies that help to restore age-related loss of function and enhance neurological recovery in preclinical models of acquired brain injury.
Long-term goals of the Tsvetkov lab are to understand how the brain changes during aging and whether these changes can be managed to slow aging and blunt neurodegeneration. Aging is a very complex phenomenon, and its mechanisms are poorly understood. While some individuals age healthily, others suffer from dementia, memory loss and behavior changes. Discovering coping, pathogenic and incidental mechanisms in different types of aging will provide insights and enhance our understanding of aging.
Dr. Urayama employs optical imaging and scanning probe microscopy to investigate the physiology and pathophysiology of the neurovascular unit in the brain. The lab’s focus is investigating how brain endothelial cells respond to endogenous and exogenous stimulation in primary cultures derived from young and aged model animals and clinical samples. Dr. Urayama’s group routinely uses isolated primary endothelial and glial cells to perform live imaging. His laboratory has extensive expertise in the primary culture of the BBB and mural cells, animal models for Alzheimer’s disease (AD), cerebral amyloid antipathy (CAA), and lysosomal storage disease (LSD).
Dr. Venna’s research program primarily focuses on two major research directions, the identification and development of novel therapeutic approaches to improve ischemic stroke outcomes by reducing neuronal death to enhance recovery, one that is currently being developed for clinical use, and the other is understanding the role of pre-stroke and post-stroke depression on recovery. His laboratory utilizes a variety of rodent models to explore the mechanisms underlying post-stroke depression and cognitive impairment. His laboratory is currently performing detailed and relevant studies to develop efficacious therapeutic interventions for use in stroke survivors.