Zhigang He, Ph.D., B.M.
The He laboratory aims to develop functional restoration strategies after CNS injury and diseases such as spinal cord injury (SCI), glaucoma, and traumatic brain injury (TBI).
A major cause of permanent functional deficits after CNS injuries and diseases is the loss of long-projecting axons. Two prominent examples are the axons of spinal projection neurons (SPNs), which connect the brain to the spinal cord and are frequently damaged after spinal cord injury (SCI), and the axons of retinal ganglion cells (RGCs), which relay all visual information from the eye to the brain and are injured after glaucoma and TBI. Depending on the type and severity of injury, different proportions of these axons may be affected. Unfortunately, injured CNS axons do not spontaneously regenerate, while spared axons often undergo compensatory but incomplete adaptations. Therefore, our laboratory focuses on two complementary therapeutic strategies: promoting regeneration of injured axons and enhancing the function of spared circuits.
Promoting axon regeneration. Our prior work has demonstrated the critical role of neuronal intrinsic growth capacity in enabling regeneration. Specifically, we identified the PTEN/mTOR and SOCS3/STAT pathways as key regulators of intrinsic regenerative ability in CNS neurons. Manipulating these signaling pathways leads to robust axon regeneration after spinal cord and optic nerve injuries in experimental models. Our ongoing studies aim to translate these findings into clinically relevant strategies and to further elucidate the molecular and cellular mechanisms that govern intrinsic regenerative potential.
Enhancing the function of spared axons. To improve functional outcomes even when full regeneration is not achievable, we explore ways to modulate spinal cord excitability and selectively engage spared pathways. Previously, we identified injury-induced down-regulation of KCC2 as a key driver of altered excitability in the injured spinal cord. Restoring KCC2 activity can re-establish responsiveness to spared descending inputs. In parallel, we are systematically dissecting the roles of specific SPN subpopulations to guide the development of targeted deep-brain stimulation (DBS) strategies aimed at tailored functional restoration after SCI.
Together, these research directions aim to yield therapeutic approaches with near-term translational potential for SCI and other CNS disorders.
Biosketch
Zhigang He is a Professor of Neurology and Ophthalmology at Harvard Medical School and the Director of the Viral Core at Boston Children’s Hospital. He received his Ph.D. from the University of Toronto and completed his postdoctoral training at the University of California, San Francisco. Dr. He is a Klingenstein Fellow in Neuroscience, a John Merck Scholar, and a McKnight Scholar. In 2019, he received the Reeve-Irvine Research Medal in recognition of his pioneering contributions to spinal cord injury research. In 2021, he was elected to the National Academy of Medicine.