CA2464474A1 - Measurement of protein synthesis rates in humans and experimental systems by use of isotopically labeled water - Google Patents

Measurement of protein synthesis rates in humans and experimental systems by use of isotopically labeled water Download PDF

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Publication number
CA2464474A1
CA2464474A1 CA002464474A CA2464474A CA2464474A1 CA 2464474 A1 CA2464474 A1 CA 2464474A1 CA 002464474 A CA002464474 A CA 002464474A CA 2464474 A CA2464474 A CA 2464474A CA 2464474 A1 CA2464474 A1 CA 2464474A1
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proteins
peptides
labeled
individual
label
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CA2464474C (en
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Marc K. Hellerstein
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University of California
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6848—Methods of protein analysis involving mass spectrometry
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Microbiology (AREA)
  • Cell Biology (AREA)
  • Food Science & Technology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Bioinformatics & Computational Biology (AREA)
  • Biophysics (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Endocrinology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)

Abstract

Provided herein are methods for measuring protein biosynthesis by using 2H2O
or radioactive 3H2O and applicable uses thereof.

Claims (37)

1. A method of determining the biosynthetic rate of one or more proteins or peptides in an individual comprising the steps of:
(a) administering labeled water to an individual over a period of time sufficient for the label of said labeled water to be incorporated into said one or more proteins or peptides to form labeled and unlabeled proteins or peptides wherein said label is selected from the group consisting of 2H, 3H, and 18 O;
(b) obtaining one or more bodily tissues or fluids from said individual, wherein said bodily tissues or fluids comprise said one or more labeled and unlabeled proteins or peptides; and (c) detecting the incorporation of said label in said one or more labeled proteins or peptides to determine the biosynthetic rate of said one or more proteins or peptides.
2. The method of claim 1 wherein said label is 2 H.
3. The method according to claim 1 comprising the additional step of partially purifying said one or more labeled and unlabeled proteins or peptides from said bodily tissues or fluids before step (c).
4. The method according to claim 1 wherein step (c) includes detection of said one or more labeled or unlabeled proteins or peptides by mass spectrometry.
5. The method according to claim 1 wherein step (c) includes detection of said one or more labeled or unlabeled proteins or peptides by liquid scintillation counting.
6. The method according to claim 1 wherein said labeled water is administered orally.
7. The method according to claim 1 wherein:
following step (b), the method includes the additional step of hydrolyzing said one or more proteins or peptides to produce hydrolyzed amino acids, and optionally, oligoproteins.
8. The method according to claim 7, wherein:
step (c) includes detecting incorporation of said label into said amino acids or oligopeptides.
9. The method according to claim 7, wherein said hydrolyzed amino acids or oligopeptides are separated by gas chromatography or HPLC.
10. The method according to claim 1 wherein said individual is a human.
11. A method of determining the biosynthetic rate of one or more proteins or peptides in an individual comprising the steps of (a) administering labeled water to an individual over a period of time sufficient for the label of said labeled water to be incorporated into said one or more proteins or peptides and thereby form labeled and unlabeled proteins or peptides wherein said label is selected from the group consisting of 2 H, 3 H, and 18 O;

(b) obtaining one or more bodily tissues or fluids from said individual, wherein said bodily tissues or fluids comprise said one or more labeled and unlabeled proteins or peptides;
(c) hydrolyzing said one or more labeled and unlabeled proteins to produce one or more labeled and unlabeled amino acids; and (d) detecting the incorporation of said one or more isotopes in said one or more labeled amino acids to determine the biosynthetic rate of said one or more proteins or peptides.
12. The method of claim 11 wherein said label is 2H.
13. The method according to claim 1 l, wherein said hydrolyzed amino acids or oligopeptides are separated by gas chromatography or HPLC.
14. The method according to claim 11 wherein said one or more proteins or peptides are selected from the group consisting of full length proteins or peptide fragments of bone collagen, liver collagen, lung collagen, cardiac collagen, muscle myosin, serum hormone, plasma apolipoproteins, serum albumin, clotting factor, immunoglobulin, and mitochondrial protein.
15. The method of claim 11 wherein said individual is a human.
16. A method of determining the degradation rate of one or more proteins or peptides in an individual comprising the steps of (a) administering labeled water to an individual over a period of time sufficient for the label of said labeled water to be incorporated into said one or more proteins or peptides to form labeled and unlabeled proteins or peptides wherein said label is selected from the group consisting of 2H, 3H, and 18O;
(b) discontinuing said administering step (a);
(c) obtaining one or more bodily tissues or fluids from said individual, wherein said bodily tissues or fluids comprise said one or more labeled and unlabeled proteins or peptides; and (d) detecting the incorporation of said one or more isotopes in said one or more labeled amino acids to determine the degradation rate of said one or more proteins or peptides.
17. The method of claim 16 wherein said label is 2H.
18. The method according to claim 16, comprising the additional step of partially purifying said one or more proteins or peptides from said bodily tissues or fluids before step (d).
19. The method according to claim 16 wherein said one or more proteins or peptides are detected by mass spectrometry or liquid scintillation counting.
20. The method according to claim 16 wherein said labeled water is administered orally.
21. The method according to claim 16 wherein:
following step (b), the method comprises the additional step of hydrolyzing said one or more proteins or peptides to produce hydrolyzed amino acids and, optionally, oligoproteins.
22. The method according to claim 16, wherein said individual is a human.
23. The method according to claim 16 wherein said one or more proteins or peptides are selected from the group consisting of full length proteins or fragments of bone collagen, liver collagen, lung collagen, cardiac collagen, muscle myosin, serum hormone, plasma apolipoproteins, serum albumin, clotting factor, immunoglobulin, and mitochondrial protein.
24. A method of determining the degradation rate of one or more proteins or peptides in an individual comprising:
a) administering labeled water to an individual over a period of time sufficient for the label of said labeled water to be incorporated into said one or more proteins or peptides to form labeled and unlabeled proteins or peptides wherein said label is selected from the group consisting of 2H, 3H, and 18O;
(b) discontinuing said administering step (a);

(c) obtaining one or more bodily tissues or fluids from said individual, wherein said bodily tissues or fluids comprise said one or more labeled and unlabeled proteins or peptides;
(d) hydrolyzing said one or more labeled and unlabeled proteins or peptides to produce one or more labeled or unlabeled amino acids; and (e) detecting the incorporation of said label in said one or more labeled amino acids to determine the degradation rate of said one or more proteins or peptides.
25. The method of claim 24 wherein said label is 2H.
26. The method according to claim 24, wherein said hydrolyzed amino acids or oligopeptides are separated by gas chromatography or HPLC.
27. The method of claim 24 wherein said individual is a human.
28. A method for identifying the risk of osteoporesis comprising determining the biosynthesis rate of bone collagen by the method of claim 1 or the degradation rate of bone collagen by the method of claim 16, wherein said one or more proteins or peptides comprise bone collagen.
29. A method for identifying a response to hormone replacement therapy comprising determining the biosynthesis rate of bone collagen by the method of claim 1 or the degradation rate of bone collagen by the method of claim 16, wherein said one or more proteins or peptides comprise bone collagen.
30. A method for identifying a response to treatment with a hypolipidemic agent comprising determining the biosynthesis rate by the method of claim 1 or the degradation rate by the method of claim 16, wherein said one or more proteins or peptides comprise apolipoprotein B.
31. A method for identifying a response to an exercise training or medical rehabilitation regimen comprising determining the biosynthesis rate by the method of claim 1 or the degradation rate by the method of claim 16, wherein said one or more proteins comprise one or more muscle proteins.
32. A method for determining an index of hypertrophy versus hyperplasia comprising measuring the ratio of protein: DNA synthesis rates in a tissue determining the biosynthesis rate by the method of claim 1 or the degradation rate by the method of claim 16.
33. A method for identifying the presence or titer of a specific immunoglobulin in an individual after vaccination or after an infectious exposure comprising determining the biosynthesis rate by the method of claim 1 or the degradation rate by the method of claim 16, wherein said one or more proteins or peptides comprises one or more immunoglobulins.
34. A kit for determining the biosynthetic rate or degradation rate of one or more proteins or peptides in an individual comprising:
a) labeled water, b) instructions for use of the kit, wherein the kit is used to determine the biosynthetic rate or degradation rate of one or more proteins or peptides in an individual.
35. The kit of claim 34 further comprising chemical compounds for isolating proteins from urine, bone, or muscle.
36. The kit of claim 34 further comprising a tool for administration of labeled water.
37. The kit of claim 34 further comprising an instrument for collecting a sample from the subject.
CA2464474A 2001-10-24 2002-10-23 Measurement of protein synthesis rates in humans and experimental systems by use of isotopically labeled water Expired - Lifetime CA2464474C (en)

Applications Claiming Priority (3)

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US33502901P 2001-10-24 2001-10-24
US60/335,029 2001-10-24
PCT/US2002/033996 WO2003061479A1 (en) 2001-10-24 2002-10-23 Measurement of protein synthesis rates in humans and experimental systems by use of isotopically labeled water

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EP (1) EP1437966B1 (en)
JP (1) JP2005515452A (en)
AT (1) ATE502578T1 (en)
AU (1) AU2002365268B2 (en)
CA (1) CA2464474C (en)
DE (1) DE60239552D1 (en)
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