Vanilloid receptor-related nucleic acids and polypeptides
AssigneesIRM LLC, a Delaware LLC, Novartis AG
InventorsStuart Bevan, Pamposh Ganju, Peter McIntyre, Ardem Patapoutian, Andrea Peier, Chuanzheng Song
Life of this patent
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Abstract
This invention provides novel genes and polypeptides of the VR family, identification of trkA+ pain specific genes expressed in the DRG, and use of these genes and polypeptides for the treatment of pain and identification of agents useful in the treatment of pain.
Claims168
An isolated TRPV3 nucleic acid molecule comprising a member selected from the group consisting of:
- a) a polynucleotide that encodes a mouse TRPV3 protein comprising amino acid residues 1-791 of SEQ ID NO:
- 2;
- b) a polynucleotide that encodes a mouse TRPV3 protein comprising amino acid residues 2-791 of SEQ ID NO:
- 2;
- c) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a mouse TRPV3 protein;
- d) a polynucleotide that encodes a human TRPV3 protein comprising amino acid residues 1-791 of SEQ ID NO 5;
- e) a polynucleotide that encodes a human TRPV3 protein comprising amino acid residues 2-791 of SEQ ID NO 5;
- f) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a human TRPV3 protein;
- and
- g) a polynucleotide that is complementary to a polynucleotide of a) through f).
An isolated TRPV3 polypeptide comprising a member selected from the group consisting of:
- a) a mouse TRPV3 protein comprising amino acid residues 1-791 of SEQ ID NO:
- 2;
- b) a mouse TRPV3 protein comprising amino acid residues 2-791 of SEQ ID NO:
- 2;
- c) one or more functional domains of a mouse TRPV3 protein;
- d) a human TRPV3 protein comprising amino acid residues 1-791 of SEQ ID NO 5;
- e) a human TRPV3 protein comprising amino acid residues 2-791 of SEQ ID NO 5;
- and
- f) one or more functional domains of a human TRPV3 protein.
A method of reducing pain associated with TRPV3 activity, the method comprising administering to a subject suffering from pain an analgesically effective amount of a compound that reduces TRPV3-mediated cation passage through a membrane or reduces signal transduction from a TRPV3 polypeptide to a DRG neuron.
A method for determining whether pain in a subject is mediated by TRPV3, the method comprising:
- a) obtaining a sample from a region of the subject at which the pain is felt;
- and
- b) testing the sample to determine whether a TRPV3 polypeptide or TRPV3 polynucleotide is present in the sample.
An isolated TRPV4 nucleic acid molecule comprising a member selected from the group consisting of:
- a) a polynucleotide that encodes a mouse TRPV4 protein comprising amino acid residues 1-871 of SEQ ID NO:
- 14;
- b) a polynucleotide that encodes a mouse TRPV4 protein comprising amino acid residues 2-871 of SEQ ID NO:
- 14;
- c) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a mouse TRPV4 protein;
- d) a polynucleotide that encodes a human TRPV4 protein comprising amino acid residues 1-871 of SEQ ID NO 17;
- e) a polynucleotide that encodes a human TRPV4 protein comprising amino acid residues 2-871 of SEQ ID NO 17;
- f) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a human TRPV4 protein;
- and
- g) a polynucleotide that is complementary to a polynucleotide of a) through f).
An isolated TRPV4 polypeptide comprising a member selected from the group consisting of:
- a) a mouse TRPV4 protein comprising amino acid residues 1-871 of SEQ ID NO:
- 14;
- b) a mouse TRPV4 protein comprising amino acid residues 2-871 of SEQ ID NO:
- 14;
- c) one or more functional domains of a mouse TRPV4 protein;
- d) a human TRPV4 protein comprising amino acid residues 1-871 of SEQ ID NO 17;
- e) a human TRPV4 protein comprising amino acid residues 2-871 of SEQ ID NO 17;
- and
- f) one or more functional domains of a human TRPV4 protein.
A method of reducing pain associated with TRPV4 activity, the method comprising administering to a subject suffering from pain an analgesically effective amount of a compound that reduces TRPV4-mediated cation passage through a membrane or reduces signal transduction from a TRPV4 polypeptide to a DRG neuron.
A method for determining whether pain in a subject is mediated by TRPV4, the method comprising:
- a) obtaining a sample from a region of the subject at which the pain is felt;
- and
- b) testing the sample to determine whether a TRPV4 polypeptide or TRPV4 polynucleotide is present in the sample.
An isolated TRPM8 nucleic acid molecule comprising a member selected from the group consisting of:
- a) a polynucleotide that encodes a mouse TRPM8 protein comprising amino acid residues 1-1104 of SEQ ID NO:
- 8;
- b) a polynucleotide that encodes a mouse TRPM8 protein comprising amino acid residues 2-1104 of SEQ ID NO:
- 8;
- c) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a mouse TRPM8 protein;
- d) a polynucleotide that encodes a human TRPM8 protein comprising amino acid residues 1-1268 of SEQ ID NO 11;
- e) a polynucleotide that encodes a human TRPM8 protein comprising amino acid residues 2-1268 of SEQ ID NO 11;
- f) a polynucleotide that encodes a polypeptide that comprises one or more functional domains of a human TRPM8 protein;
- and
- g) a polynucleotide that is complementary to a polynucleotide of a) through f).
An isolated TRPM8 polypeptide comprising a member selected from the group consisting of:
- a) a mouse TRPM8 protein comprising amino acid residues 1-1104 of SEQ ID NO:
- 8;
- b) a mouse TRPM8 protein comprising amino acid residues 2-1104 of SEQ ID NO:
- 8;
- c) one or more functional domains of a mouse TRPM8 protein;
- d) a human TRPM8 protein comprising amino acid residues 1-1268 of SEQ ID NO 11;
- e) a human TRPM8 protein comprising amino acid residues 2-1268 of SEQ ID NO 11;
- and
- f) one or more functional domains of a human TRPM8 protein.
A method of reducing pain associated with TRPM8 activity, the method comprising administering to a subject suffering from pain an analgesically effective amount of a compound that reduces TRPM8-mediated cation passage through a membrane or reduces signal transduction from a TRPM8 polypeptide to a DRG neuron.
A method for determining whether pain in a subject is mediated by TRPM8, the method comprising:
- a) obtaining a sample from a region of the subject at which the pain is felt;
- and
- b) testing the sample to determine whether a TRPM8 polypeptide or TRPM8 polynucleotide is present in the sample.
A method for identifying an agent useful in the modulation of a mammalian sensory response, the method comprising:
- a) contacting a candidate agent with a test system that comprises a receptor polypeptide selected from the group consisting of TRPM8, TRPV3 and TRPV4;
- and
- b) detecting a change in activity of the receptor polypeptide in the presence of the candidate agent as compared to the activity of the receptor polypeptide in the absence of the agent, thereby identifying an agent that modulates receptor activity.
A method for monitoring the efficacy of a treatment of a subject suffering from pain, the method comprising:
- a) obtaining, at two or more time points in the course of treatment for pain, a sample from a region of the subject at which the pain is felt;
- and
- b) testing the samples to determine whether a reduction is observed from one time point to another in amount or activity of one or more members selected from the group consisting of:
- a TRPV3 polypeptide, a TRPV3 mNRA, a TRPV4 polypeptide, a TRPV4 mNRA, a TRPM8 polypeptide, and a TRPM8 mRNA.
An assay capable of detecting the expression of one or more of TRPV3, TRPV4 or TRPM8 in human tissue, the assay selected from the group consisting of:
- a) an assay comprising contacting a human tissue sample with monoclonal antibodies binding to TRPV3, TRPV4 or TRPM8 and determining whether the monoclonal antibodies bind to polypeptides in the sample;
- and
- b) an assay comprising contacting a human tissue sample with an oligonucleotide that is capable of hybridizing to a nucleic acid that encodes TRPV3, TRPV4 or TRPM8.
A method of treating pain, the method comprising identifying a patient suffering from pain mediated by one or more polypeptides selected from the group consisting of TRPV3, TRPV4 and TRPM8 by measuring expression of the polypeptide in tissue from such patient, and administering to such patient an analgesically effective amount of an agent which inhibits the polypeptide.
A method for identifying an agent useful in the treatment of pain, the method comprising:
- a) administering a candidate agent to a mammal suffering from pain;
- b) in a sample obtained from the mammal, detecting an activity or amount of one or more members selected from the group consisting of:
- a TRPV3 polypeptide, a TRPV3 mNRA, a TRPV4 polypeptide, a TRPV4 mNRA, a TRPM8 polypeptide, and a TRPM8 mNRA;
- and
- c) comparing the amount or activity of the member in the presence of the candidate agent with the amount or activity of the member in a sample obtained from the mammal in the absence of the candidate agent, wherein a decrease in amount or activity of the member in the sample in the presence of the candidate agent relative to the amount or activity in the absence of the candidate agent is indicative of an agent useful in the treatment of pain.
A method of identifying an agent that binds to and/or modulates the activity of an mNRA or polypeptide encoded by a TRPV3, TRPV4, or TRPM8 nucleic acid, the method comprising:
- a) contacting an isolated cell which expresses a heterologous TRPV3, TRPV4, or TRPM8 nucleic acid encoding a polypeptide with the agent;
- and
- b) determining binding and/or modulation of the activity of the mNRA or polypeptide by the agent, to identify agents which bind with and/or modulate the activity of the polypeptide.
Dependencies are inferred from the claim text.