Neural modulation and the control of skeletal health and brain/skeletal signaling after injury
The Horner Laboratory uses epidural and peripheral nerve multielectrode arrays to promote spinal and cortical circuit plasticity in models of spinal cord injury. Combined with transplantation of engineered excitatory neurons, neuromodulation offers hope of creating functional pathways to restore locomotion after stroke or injury. A seminal new concept being explored to address dysfunction of the musculoskeletal system that typically accompanies brain and spinal cord damage is the alteration of autonomic control of bone microenvironment.
Research in the Elefteriou laboratory indicates that sympathetic input to bone cells is critical for growth and maintenance. Further, there is an evolving understanding of a network of brain-stem neurokines that promote bone remodeling and a reciprocal network of bone-derived hormones that impact brain health. This project seeks to model how motor and/or autonomic neuromodulation effects bone remodeling in the brain and bone hormone network. The Horner and Elefteriou laboratories will collaborate to measure bone marrow activation, bone signaling, and central neural signals that change due to neuromodulation in a model of spinal cord injury.
Biomimetic nanoparticles to promote neural connectivity
This project combines human pluripotent stem cell-derived neural cell types (Krencik Laboratory) with lipid-based nanoparticles (Tasciotti Laboratory) to yield novel biomimetic nanoparticles that can target and deliver functional payloads to the brain and promote neuronal synapse formation post-injury. These nanoparticles will be validated using an in vitro human organoid culture platform during physiological recordings. Furthermore, biodistribution of nanoparticles will be assessed within animal models. The new tool set produced in this project will have high potential to translate into a brain delivery system, and it overcomes current limitations of cellular transplantation-based therapy.
Defining the functional consequence of astrocyte activity upon neural networks
Astrocytes are highly abundant throughout the nervous system, yet their dynamic contributions to neural network activity are still not well understood. This project manipulates astrocyte activity and assesses the consequence upon synaptic physiology. Baseline neural spike frequencies will be measured within human pluripotent stem cell-derived organoids over time on multielectrode arrays, and the consequence of astrocyte activation will be assessed after chemogenetic activation as well as over expression of master gliogenic transcriptional regulators (Krencik Laboratory).
In parallel, astrocyte states will be manipulated, using transgenic mouse models, and similar physiological measurements will be conducted (Deneen Laboratory). Astrocytes in both models will be profiled with RNA sequencing to uncover potential mechanisms underlying astrocyte activity-induced neuronal communication. It is expected that high priority intercellular signaling pathways will be identified to translate into preclinical testing regarding restoring normative function that is dysregulated in inflammatory environments post-injury and post-disease.
Manipulation of RNA compartmentalization to facilitate regenerative responses
Spatiotemporal gene expression varies in cell types and specifies differential physiological function. However, how the transcriptome is compartmentalized in subcellular domains for axon maintenance, presynaptic plasticity and injury response remains unclear. In this project, the roles of RNA modifications underpinning RNA subcellular localization will systematically be revealed and de novo spatial gene expression patterns associated with regenerative capacity will be identified (Weng Laboratory).
Top candidates will be manipulated in mouse spinal cord injury models to assess their function in promoting axon regeneration (Horner Laboratory). Data gained from this systematic analysis and functional validation will offer new opportunities for the development of effective RNA therapy and treatment strategies for spinal cord and brain injury.
Spinal neuromodulation and recovery of bladder control after injury
The Sayenko Laboratory pursues the questions regarding the extent to which electrical spinal cord stimulation can neuromodulate spinal circuitry to recover motor and autonomic functions. Epidural and transcutaneous electrical spinal cord stimulation techniques are becoming more valuable as electrophysiological and clinical tools. Dimitry Sayenko, MD, PhD investigated the level of neurophysiological and functional specificity that can be achieved in selective neuromodulation of spinal networks using both methods. Rose Khavari, MD’s research efforts have led to the development of a unique and detailed functional imaging protocol that is combined with urodynamic testing, which pinpoints structural and functional brain control of bladder function.
This project will combine advanced neuroimaging approaches, urodynamics, and non-invasive spinal neuromodulation to identify the patterns of supraspinal-spinal activation and connectivity during the initiation, maintenance, and completion of voiding (or attempt of voiding) in intact, or paralyzed due to spinal cord injury and multiple sclerosis, subjects and to elucidate the neuromodulatory mechanisms of spinal stimulation on bladder control. The central hypothesis is that neural activation profiles can be used to selectively target specific regions within the central nervous system using spinal neuromodulation. Thus, the spinal and supraspinal effects of transcutaneous spinal stimulation on voiding will be examined.
Modulating the gut microbiome to reduce neurodegeneration
The Villapol Laboratory has established a research program that studies the brain-gut microbiome axis and its interactions in response to a disease. They combine techniques specific to neuropathological analysis, identification of central or peripheral markers of inflammation, bioinformatic characterization of microbial diversity and strain-level analysis, and the administration of probiotics to modulate the gut microbiome.
The laboratory of Dr. Chin is devoted to characterizing patterns of brain activity in mice and correlated neuronal activity with performance in behavioral paradigms that test different aspects of memory and cognition, especially using animal models of Alzheimer's disease (AD). Furthermore, the relationship between the microbiome and the development of cognitive impairment in dementia or the development of AD is unknown. This project will deplete the microbiome in AD animals and will restore it with the pre-AD microbiome. Specifically, the Villapol and Chin laboratories will identify the link between the modulation of the microbiome in AD mice and brain connectivity, amyloid beta accumulation, and memory impairment, with the goal of identifying novel treatments to restore cognition and behavior in neurodegenerative diseases.
Matthew Hogan, PhD
Matt Hogan is a member of the first NeuralCODR cohort. His primary mentor is Philip Horner, PhD, (Nervous System and Peripheral Organ Disorders), in whose laboratory he completed his first-year focal project and is currently continuing his NeuralCODR training. His secondary mentor is John Cooke, MD, PhD, (Neural Innervation and Organ Engineering). Hogan’s goals are to apply his engineering training in the vascular system to that of neural stimulation paradigms for neural plasticity. The Horner Laboratory provides Hogan training in small animal physiology, injury modeling and the rigorous assessment of plasticity. Cooke is mentoring Hogan on in vitro cell engineering and the role of immune regulatory pathways that drive cellular plasticity. Finally, Hogan’s clinical experience with Gavin W. Britz, MBBCh, MPH, MBA, FAANS, has focused on learning how to perform electrical implantations. This cross-disciplinary training has forged Hogan’s project into an exciting intersection of the role of neural activity and neuronal plasticity after brain injury.
Caroline Cvetkovic, PhD
Caroline Cvetkovic, PhD, is a member of the first NeuralCODR cohort. Her primary mentor is Robert C. Krencik, PhD (Neural Development and Tools). Cvetkovic completed her first-year focal project in the Krencik Laboratory where she is currently continuing her NeuralCODR training. Her secondary mentor is Sonia Villapol, PhD (Disease Disorders/Brain & Peripheral Organ), and Gavin W. Britz, MBBCh, MPH, MBA, FAANS, serves as her clinical advisor for stroke modeling techniques. Cvetkovic’s graduate expertise is in bioengineering, notably developing nano-bots. She is currently working on two exciting projects, both informed by the interdisciplinary training that she received through the NeuralCODR program. Cvetkovic is developing methods to stimulate human-stem derived organoids to study the role of neural activity in brain development and secondarily, she has developed an early model system of bowel organoids with innervation by human-derived neurons.