KLF family members regulate intrinsic axon regeneration ability
This invention relates, to a method for promoting CNS axon regeneration, comprising (1) inhibiting the expression or activity in a neuron of one or more of the members of the Krüppel-like transcription factor (KLF) family that suppress axon growth (e.g., KLF 1, 2, 3, 4, 5, 9,12, 13, 14, 15 and/or 16), and/or (2) stimulating the expression or activity in a neuron of one or more of the members of the KLF family that promote axon growth (e.g., KLF 6 and/or 7).
1. A method for promoting CNS axon regeneration, comprising
contacting a neuron with an effective amount of an agent that inhibits the expression or activity of one or more of the members of the Krüppel-like transcription factor (KLF) family that suppress axon growth, and/or
contacting a neuron with an effective amount of an agent that stimulates the expression or activity in a neuron of one or more of the members of the KLF family that promote axon growth.
2. The method of claim 1 , which is carried out in vitro.
3. The method of claim 1 , which is carried out in vivo.
4. The method of claim 1 , which is carried out in a mammal.
5. The method of claim 1 , which is carried out in a human.
6. The method of claim 1 , wherein the stimulation of expression is achieved by contacting the neuron with an effective amount of a plasmid which overexpresses a nucleic acid encoding the family member, or by introducing into the neuron the KLF family member or an active fragment thereof.
7. The method of claim 6 , wherein the plasmid which overexpresses a nucleic acid encoding the family member is contacted with the neuron by transfection.
8. The method of claim 1 , wherein the stimulation of expression is achieved by contacting the neuron with an effective amount of an agent that enhances the effect of a KLF protein that promotes axon growth.
9. The method of claim 8 , wherein the agent enhances DNA binding or the recruitment of co-factors.
10. The method of claim 1 , wherein the neuron is contacted with an effective amount of an agent that stimulates expression or activity in a neuron of one or more members of the KLF family that promotes axon growth, selected from
KLF 6 and 7.
11. The method of claim 1 , wherein the neuron is contacted with an effective amount of an agent that inhibits expression or activity in a neuron of one or more members of the KLF family that suppresses axon growth, selected from KLFs 1, 2, 3, 4, 5, 9, 12, 13, 14, 15 and 16.
12. The method of claim 11 , further comprising contacting the neuron with an effective amount of an agent that stimulates the expression and/or activity of KLF 6 and/or 7.
13. The method of any one of claim 11 , wherein the inhibition of expression is achieved by contacting the neuron with an effective amount of a small interfering RNA (siRNA), microRNA (miRNA), ribozyme, or antisense oligonucleotide that is specific for a nucleic acid encoding the KLF family member.
14. The method of claim 11 , wherein the inhibition of activity is achieved by contacting the neuron with an effective amount of a dominant negative form of the KLF family member, a recombinant construct that expresses a dominant negative form of the KLF family member; or an antibody or an aptamer that is specific for the KLF family member.
15. The method of claim 11 , which is carried out in vitro.
16. The method of claim 11 , which is carried out in vivo.
17. The method of claim 11 , which is carried out in a mammal.
18. The method of claim 11 , which is carried out in a human.
19. A method for identifying an agent that promotes CNS axon regeneration, comprising contacting neurons with candidate agents, and screening the candidate agents for their ability
to decrease the expression or activity in a neuron of one or more of the members of the Kruppel-like transcription factor (KLF) family that suppress axon growth, and/or
to increase the expression or activity in a neuron of one or more of the members of the KLF family that promote axon growth.
20. The method of claim 19 , wherein the candidates are screened for their ability to increase expression or activity in a neuron of one or more members of the KLF family that promote axon growth, selected from KLF 6 and 7.
21. The method of claim 19 , wherein candidate agents are screened for their ability to decrease the expression or activity in a neuron of one or more of the members of the KLF family that suppress axon growth, selected from KLFs 1, 2, 3, 4, 5, 9, 13, 13, 15 and/or 16.