SUMMARY
The research of Charles L. Howe, Ph.D., is focused on discovering, characterizing, understanding and therapeutically manipulating the immunological responses to trauma, injury, loss of homeostasis, degeneration, autoimmunity and infection in the central nervous system with the goal of protecting neurons, axons and neural circuits.
Dr. Howe's Translational Neuroimmunology Lab is committed to understanding how to protect and preserve functional axons and neural circuits in the face of inflammation, myelin loss, autoimmune and innate immune infiltration, structural damage, trauma, infarct, and other neurological insults.
The lab uses a unique repertoire of tools, therapeutic agents and model systems to identify and characterize cells, molecules and signals that are involved in shaping the inflammatory environment around axons, neurons and synapses during neurological insult.
The goal of Dr. Howe's lab is to learn how to manipulate and modulate this inflammatory milieu in order to maintain and recover neural function. The lab's primary hypothesis that preservation of even a subset of axons and synaptic connections during chronic demyelination, inflammation, tissue remodeling, scarring and healing, or during the immediate aftermath of seizures, spinal cord injury, trauma or stroke, will maintain a substrate for restorative, regenerative and prosthetic interventions and other therapeutic strategies aimed at renormalizing neurological structure and function.
Focus areas
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Development of novel stem cell-based strategies for generating individualized patient therapies in multiple sclerosis. In order to stop progression and preserve neurologic function in patients with multiple sclerosis, Dr. Howe's lab is developing a direct method for identifying underlying pathogenic mechanisms in individual patient biospecimens, which will allow the design of individualized therapeutic strategies to stop and reverse injury in each patient.
Dr. Howe's lab is generating patient-specific neurons, oligodendrocytes and astrocytes from induced pluripotent stem cells (iPSCs) derived from skin biopsies of patients with multiple sclerosis. The lab will couple the biochemical, genetic, proteomic and metabolomic analyses of a patient's own neural cells with metabolomic and proteomic profiling of cerebrospinal fluid and blood collected from the patient over time in order to provide patient-specific insight into druggable targets unique to the individual.
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Identification of immune effectors involved in the generation of seizures and the induction of epilepsy. Curing epilepsy means either preventing the transition from individual seizure events to recurrent seizure activity, or preventing the development of seizures all together. Current therapeutic strategies for epilepsy are palliative and may not target the underlying pathogenic mechanisms responsible for epileptogenesis.
By longitudinally profiling changes in serum chemokine levels and the activation status of circulating immune cells in adult and pediatric patients in the epilepsy monitoring unit, Dr. Howe's lab has begun, in collaboration with Gregory A. Worrell, M.D., Ph.D., to build a profile of immunological effectors that may precipitate and respond to seizures.
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Discovering the mechanisms by which antigens in the brain parenchyma are transported to peripheral lymph nodes. A critical unresolved question in neuroimmunology is the identity of antigen-presenting cells that have the capacity to enter the central nervous system, take up antigen and transport the antigenic information to the lymph nodes for presentation to T cells.
The answer to this question is crucial to our understanding of acute responses to central nervous system infection, the capacity to stimulate immunity against central nervous system tumors, and chronic autoimmune responses to neural antigens in such diseases as multiple sclerosis.
Dr. Howe's lab currently studies the ability of inflammatory monocytes to fulfill this role with the ultimate goal of modulating these cells to either promote anti-tumor responses or suppress central nervous system autoimmunity.
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Uncovering the mechanistic relationship between astrocyte stress responses and granulocyte recruitment to the central nervous system in neuromyelitis optica. Preventing the loss of neurologic function that arises from tissue destruction in patients with neuromyelitis optica (NMO) requires a deeper understanding of the upstream effector pathways that contribute to such damage.
In collaboration with Claudia F. Lucchinetti, M.D., Dr. Howe's lab is currently exploring the transcriptional, proteomic and metabolomic responses triggered in astrocytes by stimulation with the pathogenic immunoglobulin present in patients with NMO.
Recent discoveries in the lab have suggested novel therapeutic interventions that may preserve function in NMO patients by short-circuiting the astrocyte danger response and renormalizing cellular homeostasis.
- Discovering the mechanisms of axon injury during optic neuritis. Dr. Howe's lab has developed new animal models of optic neuritis and optic nerve demyelination and is employing novel tools for assessing visual function and axonal integrity in live animals in order to probe the mechanisms involved in axon injury in patients with a spectrum of optic nerve-related diseases. The ultimate goal of this research is to develop innovative strategies for delivering neuro- and axo-protective factors to the eye to protect visual function.
Significance to patient care
Dr. Howe's research is relevant to the preservation and repair of neurologic function in patients with multiple sclerosis, neuromyelitis optica, seizure disorders and epilepsy. Translational goals include the development of novel therapeutic strategies to protect and repair the central nervous system by manipulating and modulating the immune response and by targeting the injury pathways and dyshomeostatic responses induced by neuroinflammation.
Professional highlights
- Director, Office of Core Shared Services, Mayo Clinic, 2023-present.
- Charter member, Clinical Neuroimmunology and Brain Tumors (CNBT) study section, National Institutes of Health, 2015-present.
- Editorial board, Scientific Reports, 2012-present.
- Fellow, American Neurological Association, 2011-present.
- Editorial board, Neurobiology of Disease journal, 2007-present.
- Associate editor, Journal of Neuroinflammation, 2007-present.
- Research award, Minnesota Partnership for Biotechnology and Medical Genomics, 2023.