Building the bridge from discovery to treatmentTranslational research is a key component of understanding and treating medical challenges. By working across the spectrum, from small animals to human subjects, this area of research transforms laboratory observations into actual treatments for the public.
Andrew Sas, MD, PhD
Role of inflammation and immunomodulation in promoting recovery after traumatic neuronal injury.
Dr. Sas’s lab studies inflammatory responses to traumatic injury of the central nervous system (CNS). Among the immune cells that accumulate at sites of traumatic neuron injury, there is a subpopulation of myeloid cells that promote neuronal survival and regeneration of injured axons. Dr. Sas and colleagues are investigating the migratory pathways that drive the recruitment of pro-regenerative myeloid cells to the CNS. Based on an increased understanding of these migratory pathways, as well as the interaction between pro-regenerative myeloid cells and injured neurons, they’re working to develop novel immunotherapies that enhance the recovery of injured neurons in the eye, optic nerve, brain and spinal cord following trauma.
Specific Grants Awarded: K08
W. David Arnold, MDTranslational neuromuscular physiology in health and disease of the neuromuscular system.
Dr. Arnold’s research centers on translational neuromuscular physiology with a particular emphasis on understanding disease mechanisms and developing treatments for age-related loss of physical function as well as genetic neuromuscular disorders. As a neuromuscular specialist, his clinical efforts are primarily directed toward the care of patients affected by myotonic dystrophy, and his research team is investigating disease mechanisms, treatments and biomarkers for improved outcomes in patients affected by myotonic dystrophy.
Jan Schwab, MD, PhD
Protection of intrinsic recovery potential after spinal cord injury, resolution of inflammation in the lesioned CNS, control of the CNS on the immune system, and disease modifying factors hindering neurological recovery.
The primary goal of Dr. Schwab’s lab is understanding the underlying mechanism of maladaptive immune response triggered by spinal cord injury (SCI). SCI can trigger a systemic “immune paralysis,” facilitating infection susceptibility and impaired discrimination between self and non-self proteins, resulting in post-traumatic autoimmunity. Both maladaptive neuro-immunological syndromes are associated with inferior repair and serve as a causal target to improve neurological recovery. My lab applies a bedside-to-bench translational approach to decipher molecular underpinnings of clinical syndromes associated with poor recovery. We have recently identified a pathological neuroendocrine reflex driving acute spinal cord injury-induced immune deficiency syndrome (SCI-IDS). Blocking this reflex reversed infection susceptibility and can lead to develop non-antibiotic anti-infective therapies. To safeguard successful translation of experimental findings back to the clinic, another interest is on developing ways to improve prediction of animal models for clinical trials, reduce inherent bias and increase value of experimental SCI research.
Stephen J. Kolb, MD, PhD
Genetic and molecular basis of motor neuron selectivity in neuromuscular diseases including amyotrophic lateral sclerosis and spinal muscular atrophy.
Dr. Kolb’s research centers on recent advances in the genetics of amyotrophic lateral sclerosis (ALS) and the emergence of therapeutic gene therapies, which has resulted in increasing optimism that there’s hope for meaningful disease-modifying therapies in genetic forms of ALS. Whole genome/exome sequencing and genome-wide association studies recently revealed that ALS-associated mutations in the C-terminal domain of the kinesin KIF5A. Dr. Kolb’s lab has created a novel mouse model of Kif5a ALS, with which the scientists will characterize the behavioral, electrophysiological and pathological changes as a first step to understand the functional consequences of KIF5A ALS-associated mutations and to create a tool for future preclinical and basic science studies.View Dr. Kolb's profile Kolb Lab
Benjamin Segal, MD
A NOVEL INFLAMMATORY CELL WITH NEUROPROTECTIVE AND NEUROREGENERATIVE PROPERTIES
Chronic or progressive disability in individuals with central nervous system (CNS) injury is secondary, in large part, to the limited regenerative capacity of nerve fibers in the optic nerve, brain, and spinal cord. The long term goal of this project is to develop novel therapeutic interventions that overcome barriers to CNS repair and promote neuronal survival and axonal regrowth, thereby mitigating, or even reversing, neurological disability. The Segal lab has discovered a novel type of immune cell that migrates to sites of CNS injury, rescues neurons from cell death, and stimulates the regrowth of severed nerve fibers. The lab is currently investigating the lineage, phenotypic characteristics, and mechanism of action of this leukocyte subset. Ultimately, this research may lead to the development of novel autologous cell therapies, and/ or immunomodulatory drugs, that induce CNS repair and drive the recovery of lost neurological functions, in individuals with a range of neurological disorders including traumatic brain and spinal cord injury, multiple sclerosis, optic neuropathy, stroke, and ALS.
ARGINASE-1 AND iNOS EXPRESSING CNS MYELOID CELL SUBSETS IN EAE AND MS
Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), is the most common cause of non-traumatic neurological disability in young adults in the Western Hemisphere. Significant progress has been made in the development of disease modifying therapies (DMT) that decrease the frequency of clinical MS relapses by blocking or depleting pathogenic lymphocytes. However, none of the approved DMT are curative, and none are effective in all patients. There are no treatments that slow, or reverse, progressive forms of MS. Myeloid cells, including macrophages, dendritic cells and microglia, comprise the majority of the immune cells that accumulate in the central nervous system (CNS) during Multiple Sclerosis (MS). Distinct CNS-infiltrating myeloid cell subsets have been implicated in damage or repair. Members of the Segal lab are studying the diversity, plasticity, biological properties, and function of CNS myeloid cells during exacerbations and remissions of experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS. With collaborators, they are also characterizing myeloid cell subsets in postmortem MS tissue. This research may lead to the identification of novel myeloid biomarkers and therapeutic targets for the management of individuals with relapsing and progressive forms of MS who do not respond to currently available treatments.
Billur Akkaya, MD, DPhil
Deciphering the antigen mediated interactions and suppression mechanisms of human Tregs
This project aims to implement a novel pipeline to reveal the specificities of dominant autoreactive effector T cell and Treg clones derived from type 1 diabetes mellitus and multiple sclerosis patients. The overarching goal of this study is to devise new antigen-targeted adoptive Treg therapies for autoimmune diseases.
Discovering the molecular machinery underlying Treg interactions and Treg-mediated suppression
This project aims to elucidate the signals provided to Tregs via antigen mediated contacts with dendritic cells. We compare Tregs and effector T cells using conventional techniques such as phosphoflow and western blot while also performing an unbiased analysis of phosphoproteome, to decipher the pathways underlying antigen- MHC Class II capture and antigen-specific suppression. Overall, this project will uncover the molecular basis of antigen-specific suppression performed by Tregs and identify key molecules that can potentially be targeted to fine-tune the Treg activity in autoimmunity and cancer.
Determining the antigen-presentation capability of antigen-specific Tregs post- primary immune synapse
In this project we focus on the events after Treg-APC synapse and investigate whether capturing antigen- MHC Class II (pMHCII) equips Tregs with the unique ability to target helper T cells during the physical absence of dendritic cells. We perform live confocal and intravital two-photon microscopy imaging as well as flow cytometry 1) to quantify direct contact between Tregs and helper T cells post-pMHCII acquisition 2) to determine modes of paracrine communication. Altogether, the findings from this project will describe how the Treg-T cell interactions shape peripheral tolerance and what mechanisms additional to pMHCII depletion are in place to prevent autoimmunity and also to promote tumor development.