Severe morbidity and mortality are commonly associated with spinal cord injury (SCI). Patients who survive frequently live with paralysis and extremely reduced quality of life and productivity. The financial and emotional burdens to patients and their caregivers are enormous. There is currently no effective cure. This is largely because SCI often results in a permanent loss of neurons and the disruption of neural circuits. For a functional recovery after SCI, the key challenge is how to restore the disrupted neuronal circuits. The long-term goal of this proposed research is to develop an innovative therapeutic strategy for SCI by using patients'endogenous cells. In response to injury, astrocytes become reactive and proliferate to form glial scars. These scars are initially beneficial by preserving th integrity of cells surrounding the damaged site. However, their persistence is detrimental to neuronal repair. Glial scars not only form a physical barrier but also secrete inhibitors of axon growth that act on surviving neurons. We hypothesize that changing the fate of these scar- forming cells to neural progenitors and/or neurons might enable self-repair of the injured spinal cord in two ways: 1) by relieving the inhibition of axon growth of surviving neurons by glial scars and 2) by the formation of bridging neural circuits through converted new neurons. Our preliminary data shows that new neurons can be induced by the ectopic expression of a single transcription factor in the adult spinal cord. The major goals of this proposal are 1) to further examine the in vivo reprogramming process in the adult spinal cord, 2) to target several genetic and epigenetic pathways to enhance the reprogramming efficiency, and 3) to optimize the reprogramming process for neuronal survival, maturation and functional integration into the local neuronal circuitry. Results from this proposal may lead to a novel therapeutic strategy for SCI, which is to let the injured spinal cord repair itself using endogenous cells.

Public Health Relevance

Spinal cord injury causes a huge financial and emotional burden to patients and their caregivers in the US. There is currently no effective cure. The proposed studies will define ways to let the injured spinal cord repair itself using the patient's endogenous cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS088095-01
Application #
8747528
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2014-06-15
Project End
2019-04-30
Budget Start
2014-06-15
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$347,813
Indirect Cost
$129,063
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Su, Z; Zang, T; Liu, M-L et al. (2014) Reprogramming the fate of human glioma cells to impede brain tumor development. Cell Death Dis 5:e1463