pulmonary fibrosis disease biomarkers

Abstract

To provide a biomarker for pulmonary fibrosis disease and a method for using the same. [Solution] A method for testing for pulmonary fibrosis, comprising the step of detecting at least one protein selected from the group consisting of protein group (A), protein group (B), protein group (C), protein group (D), protein group (E), and protein group (F) in extracellular vesicles of body fluid or a blood sample collected from a subject.

Claims

1. A method for examining pulmonary fibrosis disease, (1) Protein group (A), protein group (B), protein group (C), protein group (D), protein group (E), and protein group (F) in extracellular vesicles of bodily fluids or blood samples collected from the subject: (A) ATP-dependent RNA helicase DDX55, Secretoglobin family 3A member 1, BPI fold-containing family B member 1, Pulmonary surfactant-associated protein B, Protein argonaute-2, Pulmonary surfactant-associated protein A2; Pulmonary surfactant-associated protein A1, Testin, Copine-2, Sorting nexin-18, Transforming growth A protein group consisting of factor-beta-induced protein ig-h3 and CC motif chemokine 18, (B) A group of proteins consisting of Cyclin-dependent kinase 11B; Cyclin-dependent kinase 11A, Secretogranin-1, and Peptidyl-prolyl cis-trans isomerase A. The protein group consisting of Surfactant protein B, BPI fold containing family B member 1, Argonaute 2, RISC catalytic component, Small integral membrane protein 1 (Vel blood group), Secretoglobin family 3A member 1, Sorting nexin 18, Myelin protein zero like 1, Alpha hemoglobin stabilizing protein, Glycoprotein nmb, Yip1 interacting factor homolog B, membrane trafficking protein, Synaptogyrin 1, LDL receptor related protein 1, Cysteine rich transmembrane module containing 1, Testin LIM domain protein, Endoplasmic reticulum protein 29, Erythrocyte membrane protein band 4.2, Reticulon 4, Synaptogyrin 2, and Spectrin alpha, erythrocytic 1 (D) Cyclin dependent kinase 11A, B, FYN proto-oncogene, Src family tyrosine kinase, Peptidylprolyl isomerase A, Serpin family B member 6, Tubulin alpha 8, Sorbitol dehydrogenase, Chromogranin B, Claudin 3, Metallo-beta-lactamase domain containing 2, Inositol polyphosphate-5-phosphatase A, NGFI-A binding protein 2, BRICK1, SCAR / WAVE actin nucleating complex subunit, Tropomyosin 1, PX domain containing serine / threonine kinase like, Galectin like, Tandem C2 domains, nuclear, YKT6 v-SNARE homolog, Plexin B2, Nectin cell adhesion molecule 2, Glutathione peroxidase 4, SH3 domain binding glutamate rich protein like 2, CC motif chemokine receptor 4, S100 calcium binding A group of proteins consisting of protein A13, CD69 molecule, Spleen-associated tyrosine kinase, D-tyrosyl-tRNA deacylase 1, Acyl-CoA dehydrogenase very long chain, and Coagulation factor VII. (E) A group of proteins consisting of Surfactant protein B and LDL receptor related protein 1, and (F) A group of proteins consisting of the CD34 molecule, S100 calcium binding protein A13, and Family with sequence similarity 49 member B. A testing method comprising the step of detecting at least one protein selected from the group consisting of the following.

2. The examination method according to claim 1, wherein the pulmonary fibrosis disease is interstitial lung disease (ILD).

3. The examination method according to claim 1 or 2, wherein the pulmonary fibrosis disease is idiopathic pulmonary fibrosis (IPF).

4. The testing method according to claim 3, wherein the protein to be detected includes at least one protein selected from the group consisting of protein group (A) and protein group (B).

5. If the detected protein contains at least one protein (protein A') selected from protein group (A), then, (2A) A step in which, if the amount or concentration of protein A' detected in step (1) is equal to or greater than a cutoff value, the subject is diagnosed with idiopathic pulmonary fibrosis (IPF), has a poor prognosis for IPF, or has progressive IPF. The inspection method according to claim 3 or 4, including the method described in claim 3 or 4.

6. If the detected protein contains at least one protein (protein B') selected from protein group (B), then, (2B) A step in which, if the amount or concentration of protein B' detected in step (1) is less than or equal to a cutoff value, the subject is diagnosed with idiopathic pulmonary fibrosis (IPF), has a poor prognosis for IPF, or has progressive IPF. The inspection method according to any one of claims 3 to 5, including the method described above.

7. The examination method according to claim 1 or 2, wherein the pulmonary fibrotic disease is interstitial lung disease with progressive fibrosis (PF-ILD).

8. The testing method according to claim 7, wherein the protein to be detected includes at least one protein selected from the group consisting of protein group (C), protein group (D), protein group (E), and protein group (F).

9. If the detected protein contains at least one protein (protein CE') selected from the group consisting of protein group (C) and protein group (E), then, (2CE) A step in which, if the amount or concentration of protein CE' detected in step (1) is equal to or greater than the cutoff value, the subject is found to have progressive interstitial lung disease with progressive fibrosis (PF-ILD), has a poor prognosis for PF-ILD, or has progressive PF-ILD. The inspection method according to claim 7 or 8, including the method described in claim 7 or 8.

10. If the detected protein contains at least one protein (protein DF') selected from the group consisting of protein group (D) and protein group (F), then, (2DF) A step in which, if the amount or concentration of protein DF' detected in step (1) is less than or equal to a cutoff value, the subject is found to have progressive interstitial lung disease with progressive fibrosis (PF-ILD), has a poor prognosis for PF-ILD, or has progressive PF-ILD. The inspection method according to any one of claims 7 to 9, including the method described above.

11. The testing method according to any one of claims 1 to 10, wherein the subject is a human.

12. Protein group (A), protein group (B), protein group (C), protein group (D), protein group (E), and protein group (F): (A) ATP-dependent RNA helicase DDX55, Secretoglobin family 3A member 1, BPI fold-containing family B member 1, Pulmonary surfactant-associated protein B, Protein argonaute-2, Pulmonary surfactant-associated protein A2; Pulmonary surfactant-associated protein A1, Testin, Copine-2, Sorting nexin-18, Transforming growth A protein group consisting of factor-beta-induced protein ig-h3 and CC motif chemokine 18, (B) A group of proteins consisting of Cyclin-dependent kinase 11B; Cyclin-dependent kinase 11A, Secretogranin-1, and Peptidyl-prolyl cis-trans isomerase A. The protein group consisting of Surfactant protein B, BPI fold containing family B member 1, Argonaute 2, RISC catalytic component, Small integral membrane protein 1 (Vel blood group), Secretoglobin family 3A member 1, Sorting nexin 18, Myelin protein zero like 1, Alpha hemoglobin stabilizing protein, Glycoprotein nmb, Yip1 interacting factor homolog B, membrane trafficking protein, Synaptogyrin 1, LDL receptor related protein 1, Cysteine rich transmembrane module containing 1, Testin LIM domain protein, Endoplasmic reticulum protein 29, Erythrocyte membrane protein band 4.2, Reticulon 4, Synaptogyrin 2, and Spectrin alpha, erythrocytic 1 (D) Cyclin dependent kinase 11A, B, FYN proto-oncogene, Src family tyrosine kinase, Peptidylprolyl isomerase A, Serpin family B member 6, Tubulin alpha 8, Sorbitol dehydrogenase, Chromogranin B, Claudin 3, Metallo-beta-lactamase domain containing 2, Inositol polyphosphate-5-phosphatase A, NGFI-A binding protein 2, BRICK1, SCAR / WAVE actin nucleating complex subunit, Tropomyosin 1, PX domain containing serine / threonine kinase like, Galectin like, Tandem C2 domains, nuclear, YKT6 v-SNARE homolog, Plexin B2, Nectin cell adhesion molecule 2, Glutathione peroxidase 4, SH3 domain binding glutamate rich protein like 2, CC motif chemokine receptor 4, S100 calcium binding A group of proteins consisting of protein A13, CD69 molecule, Spleen-associated tyrosine kinase, D-tyrosyl-tRNA deacylase 1, Acyl-CoA dehydrogenase very long chain, and Coagulation factor VII. (E) A group of proteins consisting of Surfactant protein B and LDL receptor related protein 1, and (F) A group of proteins consisting of the CD34 molecule, S100 calcium binding protein A13, and Family with sequence similarity 49 member B. A diagnostic agent for pulmonary fibrosis disease comprising a detection agent for at least one protein selected from the group consisting of the following.

13. Protein group (A), protein group (C), and protein group (E): (A) ATP-dependent RNA helicase DDX55, Secretoglobin family 3A member 1, BPI fold-containing family B member 1, Pulmonary surfactant-associated protein B, Protein argonaute-2, Pulmonary surfactant-associated protein A2; Pulmonary surfactant-associated protein A1, Testin, Copine-2, Sorting nexin-18, Transforming growth A protein group consisting of factor-beta-induced protein ig-h3 and CC motif chemokine 18, (C) Surfactant protein B, BPI fold containing family B member 1, Argonaute 2, RISC catalytic component, Small integral membrane protein 1 (Vel blood group), Secretoglobin family 3A member 1, Sorting nexin 18, Myelin protein zero like 1, Alpha hemoglobin stabilizing protein, Glycoprotein nmb, Yip1 interacting factor homolog B, membrane trafficking protein, Synaptogyrin 1, LDL receptor related protein 1, Cysteine ​​rich transmembrane module containing 1, Testin LIM domain protein, Endoplasmic reticulum protein 29, Erythrocyte membrane protein band 4.2, Reticulon 4, Synaptogyrin 2, and Spectrin alpha, erythrocytic 1, and (E) A group of proteins consisting of Surfactant protein B and LDL receptor related protein 1. An inhibitor of at least one protein selected from the group consisting of, and Protein group (B), protein group (D), and protein group (F): (B) A group of proteins consisting of Cyclin-dependent kinase 11B; Cyclin-dependent kinase 11A, Secretogranin-1, and Peptidyl-prolyl cis-trans isomerase A. (D) Cyclin dependent kinase 11A, B, FYN proto-oncogene, Src family tyrosine kinase, Peptidylprolyl isomerase A, Serpin family B member 6, Tubulin alpha 8, Sorbitol dehydrogenase, Chromogranin B, Claudin 3, Metallo-beta-lactamase domain containing 2, Inositol polyphosphate-5-phosphatase A, NGFI-A binding protein 2, BRICK1, SCAR / WAVE actin nucleating complex subunit, Tropomyosin 1, PX domain containing serine / threonine kinase like, Galectin like, Tandem C2 domains, nuclear, YKT6 v-SNARE homolog, Plexin B2, Nectin cell adhesion molecule 2, Glutathione peroxidase 4, SH3 domain binding glutamate rich protein like 2, CC motif chemokine receptor 4, S100 calcium binding A group of proteins consisting of protein A13, CD69 molecule, Spleen-associated tyrosine kinase, D-tyrosyl-tRNA deacylase 1, Acyl-CoA dehydrogenase very long chain, and Coagulation factor VII, and (F) A group of proteins consisting of the CD34 molecule, S100 calcium binding protein A13, and Family with sequence similarity 49 member B. A protein enhancer selected from the group consisting of at least one protein. A preventive or therapeutic agent for pulmonary fibrotic disease, comprising at least one drug selected from the group consisting of the following.

14. Protein groups (A), (B), (C), (D), (E), and (F) in extracellular vesicles of body fluids or blood samples collected from animals treated with the test substance: (A) ATP-dependent RNA helicase DDX55, Secretoglobin family 3A member 1, BPI fold-containing family B member 1, Pulmonary surfactant-associated protein B, Protein argonaute-2, Pulmonary surfactant-associated protein A2; Pulmonary surfactant-associated protein A1, Testin, Copine-2, Sorting nexin-18, Transforming growth A protein group consisting of factor-beta-induced protein ig-h3 and CC motif chemokine 18, (B) A group of proteins consisting of Cyclin-dependent kinase 11B; Cyclin-dependent kinase 11A, Secretogranin-1, and Peptidyl-prolyl cis-trans isomerase A. The protein group consisting of Surfactant protein B, BPI fold containing family B member 1, Argonaute 2, RISC catalytic component, Small integral membrane protein 1 (Vel blood group), Secretoglobin family 3A member 1, Sorting nexin 18, Myelin protein zero like 1, Alpha hemoglobin stabilizing protein, Glycoprotein nmb, Yip1 interacting factor homolog B, membrane trafficking protein, Synaptogyrin 1, LDL receptor related protein 1, Cysteine rich transmembrane module containing 1, Testin LIM domain protein, Endoplasmic reticulum protein 29, Erythrocyte membrane protein band 4.2, Reticulon 4, Synaptogyrin 2, and Spectrin alpha, erythrocytic 1 (D) Cyclin dependent kinase 11A, B, FYN proto-oncogene, Src family tyrosine kinase, Peptidylprolyl isomerase A, Serpin family B member 6, Tubulin alpha 8, Sorbitol dehydrogenase, Chromogranin B, Claudin 3, Metallo-beta-lactamase domain containing 2, Inositol polyphosphate-5-phosphatase A, NGFI-A binding protein 2, BRICK1, SCAR / WAVE actin nucleating complex subunit, Tropomyosin 1, PX domain containing serine / threonine kinase like, Galectin like, Tandem C2 domains, nuclear, YKT6 v-SNARE homolog, Plexin B2, Nectin cell adhesion molecule 2, Glutathione peroxidase 4, SH3 domain binding glutamate rich protein like 2, CC motif chemokine receptor 4, S100 calcium binding A group of proteins consisting of protein A13, CD69 molecule, Spleen-associated tyrosine kinase, D-tyrosyl-tRNA deacylase 1, Acyl-CoA dehydrogenase very long chain, and Coagulation factor VII. (E) A group of proteins consisting of Surfactant protein B and LDL receptor related protein 1, and (F) A group of proteins consisting of the CD34 molecule, S100 calcium binding protein A13, and Family with sequence similarity 49 member B. A screening method for the active ingredient of a preventive or therapeutic agent for pulmonary fibrotic disease, using the amount or concentration of at least one protein selected from the group consisting of the following as an indicator.

15. Protein groups (A), (B), (C), (D), (E), and (F) in extracellular vesicles of body fluids or blood samples collected from animals treated with the test substance: (A) ATP-dependent RNA helicase DDX55, Secretoglobin family 3A member 1, BPI fold-containing family B member 1, Pulmonary surfactant-associated protein B, Protein argonaute-2, Pulmonary surfactant-associated protein A2; Pulmonary surfactant-associated protein A1, Testin, Copine-2, Sorting nexin-18, Transforming growth A protein group consisting of factor-beta-induced protein ig-h3 and CC motif chemokine 18, (B) A group of proteins consisting of Cyclin-dependent kinase 11B; Cyclin-dependent kinase 11A, Secretogranin-1, and Peptidyl-prolyl cis-trans isomerase A. The protein group consisting of Surfactant protein B, BPI fold containing family B member 1, Argonaute 2, RISC catalytic component, Small integral membrane protein 1 (Vel blood group), Secretoglobin family 3A member 1, Sorting nexin 18, Myelin protein zero like 1, Alpha hemoglobin stabilizing protein, Glycoprotein nmb, Yip1 interacting factor homolog B, membrane trafficking protein, Synaptogyrin 1, LDL receptor related protein 1, Cysteine rich transmembrane module containing 1, Testin LIM domain protein, Endoplasmic reticulum protein 29, Erythrocyte membrane protein band 4.2, Reticulon 4, Synaptogyrin 2, and Spectrin alpha, erythrocytic 1 (D) Cyclin dependent kinase 11A, B, FYN proto-oncogene, Src family tyrosine kinase, Peptidylprolyl isomerase A, Serpin family B member 6, Tubulin alpha 8, Sorbitol dehydrogenase, Chromogranin B, Claudin 3, Metallo-beta-lactamase domain containing 2, Inositol polyphosphate-5-phosphatase A, NGFI-A binding protein 2, BRICK1, SCAR / WAVE actin nucleating complex subunit, Tropomyosin 1, PX domain containing serine / threonine kinase like, Galectin like, Tandem C2 domains, nuclear, YKT6 v-SNARE homolog, Plexin B2, Nectin cell adhesion molecule 2, Glutathione peroxidase 4, SH3 domain binding glutamate rich protein like 2, CC motif chemokine receptor 4, S100 calcium binding A group of proteins consisting of protein A13, CD69 molecule, Spleen-associated tyrosine kinase, D-tyrosyl-tRNA deacylase 1, Acyl-CoA dehydrogenase very long chain, and Coagulation factor VII. (E) A group of proteins consisting of Surfactant protein B and LDL receptor related protein 1, and (F) A group of proteins consisting of the CD34 molecule, S100 calcium binding protein A13, and Family with sequence similarity 49 member B. A method for evaluating the inducibility or exacerbation of pulmonary fibrosis disease, using the amount or concentration of at least one protein selected from the group consisting of the following as an indicator.

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