Angelo Lepore, PhD
JHN 4th floor
Philadelphia, PA 19107
(215) 503-4358 fax
Research and Clinical Interests
Overall Goals: Our laboratory has an interest in examining the in vivo role played by astrocyte glutamate transporters in the etiology and treatment of traumatic spinal cord injury (SCI). SCI represents a debilitating group of conditions that affect approximately 1.3 million individuals in the U.S. alone, resulting in physical and psychological burdens on patients and their families and huge economic costs.
An opportunity exists for preventing secondary cell death following spinal trauma that is responsible for the majority of tissue and functional loss. One of the major causes of secondary injury is excitotoxic cell death due to dysregulation of extracellular levels of the neurotransmitter, glutamate. In the central nervous system (CNS), glutamate is efficiently cleared from the extracellular space by glutamate transporters. Astrocytes are supportive cells with crucial roles in CNS function, outnumbering their neuronal counterparts several-fold. In particular, astrocytes express the major CNS glutamate transporters, GLT1 and GLAST, and are responsible for the vast majority of CNS glutamate buffering, thereby preventing excitotoxic cell loss. Despite their critical importance in the CNS, the roles played by astrocytes in neurological disorders such as neurodegeneration and traumatic injury have not been well elucidated.
Experimental Approaches: Employing a multidisciplinary approach that includes surgical generation of various injury paradigms, transgenic and knockout mouse models, glial progenitor cell transplantation, intraspinal viral vector-based manipulation of glutamate transporter levels, and extensive histological, biochemical, behavioral and in vivo physiological analyses, our goal is to both characterize the roles played by these astrocyte glutamate transporters in clinically-relevant functional outcomes following SCI and to develop promising therapeutic strategies. In addition to glutamate transport, we are also interested in examining the role played by other astrocyte-related functions in SCI.
Glutamate Transporters and Respiratory Function: Half of human SCI cases affect cervical regions, resulting in debilitating respiratory compromise due to phrenic motor neuron loss and injury to descending bulbospinal respiratory axons. Despite its obvious and profound clinical importance, relatively few studies have evaluated maintenance of respiratory function as a viable therapy in cervical SCI models. We are interested in characterizing the role of astrocyte glutamate transporters in protection of spinal cord respiratory pathways following SCI, as well as therapeutically targeting these important circuits.
Glutamate Transporters and Neuropathic Pain: Persistent astrocyte activation is thought to also play a central role in debilitating neuropathic pain conditions such as hyperalgesia, allodynia and spontaneous pain following SCI, which occur in up to 80% of SCI patients. We are interested in evaluating the role of astrocyte glutamate transporters and compromised glutamate homeostasis in the development, maintenance, spread, and treatment of these various forms of neuropathic pain in animal models of SCI.
Stem Cell Transplantation: Given the important role of non-neuronal cell types in CNS disease, reconstitution of a functional astrocyte environment may represent a promising therapeutic approach. Our goal is to target astrocyte replacement for the treatment of SCI via transplantation of primary glial progenitors and induced pluripotent stem cell (iPS)-derived astrocytes and progenitors. To evaluate the role of astrocyte-specific functions in graft efficacy on key outcome measures such as motor function, respiratory function and neuropathic pain, glutamate transporter expression and activity in transplanted cells will be manipulated in various ways.
In addition to SCI, we are also interested in examining the role of astrocytes in the etiology and treatment of the motor neuron disease, Amyotrophic lateral sclerosis (ALS), including developing therapeutic strategies using cell transplantation to target astrocyte biology.
Most Recent Peer-Reviewed Publications
- Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons
- Mutation of the caspase-3 cleavage site in the astroglial glutamate transporter EAAT2 delays disease progression and extends lifespan in the SOD1-G93A mouse model of ALS
- Improving the therapeutic efficacy of neural progenitor cell transplantation following spinal cord injury
- MAP7 regulates axon collateral branch development in dorsal root ganglion neurons
- Harnessing the power of cell transplantation to target respiratory dysfunction following spinal cord injury
- Corticothalamic network dysfunction and behavioral deficits in a mouse model of Alzheimer's disease
- iPS cell transplantation for traumatic spinal cord injury
- GLT1 overexpression reverses established neuropathic pain-related behavior and attenuates chronic dorsal horn neuron activation following cervical spinal cord injury
- GLT1 overexpression in SOD1G93A mouse cervical spinal cord does not preserve diaphragm function or extend disease
- Functional and morphological assessment of diaphragm innervation by phrenic motor neurons
- Therapeutically targeting astrocytes with stem and progenitor cell transplantation following traumatic spinal cord injury
- Kv3.4 channel function and dysfunction in nociceptors
- Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury
- Transplantation of glial progenitors that overexpress glutamate transporter GLT1 preserves diaphragm function following cervical SCI
- Human iPS cell-derived astrocyte transplants preserve respiratory function after spinal cord injury
- Inhibiting drug efflux transporters improves efficacy of ALS therapeutics
- Persistent at-level thermal hyperalgesia and tactile allodynia accompany chronic neuronal and astrocyte activation in superficial dorsal horn following mouse cervical contusion spinal cord injury
- Chronic at-level thermal hyperalgesia following rat cervical contusion spinal cord injury is accompanied by neuronal and astrocyte activation and loss of the astrocyte glutamate transporter, GLT1, in superficial dorsal horn
- Overexpression of the astrocyte glutamate transporter GLT1 exacerbates phrenic motor neuron degeneration, diaphragm compromise, and forelimb motor dysfunction following cervical contusion spinal cord injury
- Immunohistochemical toolkit for tracking and quantifying xenotransplanted human stem cells