Devastating and persistent neurological deficits occur after Spinal Cord Injury (SCI), despite survival of nearly all neurons. The primary cause of disability is disconnection of networks by axon transection. Recovery of some movement would be adequate for patients to gain a level of independence in wheel chair transfers, bowel and bladder management, and locomotion. Today, there is no approved medical therapy for the 300,000 to 1,200,000 individuals in the USA with SCI. The CNS of adult mammals, as compared to the peripheral nervous system of mammals or the nervous system of other organisms, has extremely limited capacity for axonal regeneration. Our axonal growth studies included discovery of Nogo and Nogo Receptor (NgR1). We demonstrated their role in preventing axonal sprouting, regeneration and recovery after injury. We have demonstrated that NgR1(310)-Fc is efficacious for recovery from SCI, even when treatment starts months after damage. It is being developed for human SCI trials now. While specific factors, such as NgR1, limiting axon regeneration have been identified, they provide an incomplete explanation for poor adult mammalian CNS regeneration. We completed a genome-wide shRNA screen for endogenous genes limiting mammalian CNS axon repair. The validity of this method was demonstrated by the identification of INPP5F as a gene limiting neural repair in a pilot screen of phosphatases. One cellular pathway is bioinformatically the most enriched gene set in the mammalian screen, and also regulates regeneration in nematodes. The relevance of this pathway will be tested in preclinical models of traumatic SCI. Both gene deletion strains and pharmacological inhibition will be studied to provide a validated pathway for future therapeutic development. The findings will have high relevance for the development of novel therapeutics for SCI.

Public Health Relevance

Many neurological conditions disrupt connections between surviving neurons. The regeneration of axons has the potential to provide functional neurological recovery, without requiring ?new? cells from transplantation or from neurogenesis. Unfortunately, the CNS of adult mammals, as compared to the peripheral nervous system or nervous system of other organisms, has extremely limited capacity for axon regeneration. We have developed screening methods to identify those genes limiting the repair of axons in the mammalian CNS. We will evaluate regeneration-limiting genes using model organisms, biochemical methods and translational models of traumatic spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS097283-05
Application #
10067580
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Bambrick, Linda Louise
Project Start
2016-12-01
Project End
2024-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
5
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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