Methods Of Regulating Metabolism And Mitochondrial Function
First Claim
Patent Images
1. A method of modulating a biological response in a cell, the method comprising contacting the cell with at least one agent that modulates the expression or activity of Errα
- or Gabp, wherein the biological response is (a) expression of at least one OXPHOS gene;
(b) mitochondrial biogenesis;
(c) expression of Nuclear Respiratory Factor 1 (NRF-1);
(d) β
-oxidation of fatty acids;
(e) total mitochondrial respiration;
(f) uncoupled respiration;
(g) mitochondrial DNA replication;
(h) expression of mitochondrial enzymes;
or (i) skeletal muscle fiber-type switching.
2 Assignments
0 Petitions
Accused Products
Abstract
The invention relates to novel methods of regulating metabolism and mitochondrial biogenesis. Some aspects of the invention relate to methods of treating or preventing diseases in a patient associated with reduced mitochondrial function, to methods of identifying agents to treat such diseases, and to methods of diagnosing such diseases. Other aspects of the invention relate to a set of coordinately-regulated genes which regulate oxidative phosphorylation.
49 Citations
94 Claims
-
1. A method of modulating a biological response in a cell, the method comprising contacting the cell with at least one agent that modulates the expression or activity of Errα
- or Gabp, wherein the biological response is
(a) expression of at least one OXPHOS gene;
(b) mitochondrial biogenesis;
(c) expression of Nuclear Respiratory Factor 1 (NRF-1);
(d) β
-oxidation of fatty acids;
(e) total mitochondrial respiration;
(f) uncoupled respiration;
(g) mitochondrial DNA replication;
(h) expression of mitochondrial enzymes;
or(i) skeletal muscle fiber-type switching. - View Dependent Claims (2, 3, 4, 5, 6, 7, 11, 12, 13, 14, 15, 16)
- or Gabp, wherein the biological response is
-
8-10. -10. (canceled)
-
17. A method of determining if an agent is a potential agent for the treatment of a disorder that is characterized by glucose intolerance, insulin resistance or reduced mitochondrial function, the method comprising determining if the agent increases:
-
(i) the expression or activity of Errα
or Gabp in a cell;
or(ii) the formation of a complex between a PGC-1 polypeptide and (i) an Errα
polypeptide;
or (ii) a Gabp polypeptide;
wherein an agent that increases (i) or (ii) is a potential target for the treatment of the disorder. - View Dependent Claims (19, 20)
-
- 18. (canceled)
-
22-34. -34. (canceled)
-
35. A method of reducing the metabolic rate of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an agent which decreases the expression or activity of at least one of the following:
-
(i) Errα
;
(ii) Gabpa;
(iii) a gene having an Errα
binding site, a Gabpa binding site, or both;
or(iv) a transcriptional activator which binds to an Errα
binding site or to a Gabpa binding site;
thereby reducing the metabolic rate of the patient. - View Dependent Claims (36, 37, 38)
-
-
39-41. -41. (canceled)
-
42. A method of identifying a susceptibility locus for a disorder that is characterized by reduced mitochondrial function, glucose intolerance, or insulin intolerance in a subject, the method comprising
(i) identifying at least one polymorphisms in a gene, or linked to a gene, wherein the gene (a) has an Errα - binding site, a Gabpa binding site, or both;
or (b) is Errα
, Gabpa, or Gabpb;
(ii) determining if at least one polymorphism is associated with the incidence of the disorder, wherein if a polymorphism is associated with the incidence of the disorder then the gene having the polymorphism, or the gene to which the polymorphism is linked, is a susceptibility locus. - View Dependent Claims (43, 44, 45, 46)
- binding site, a Gabpa binding site, or both;
-
47. A method of determining if a subject is at risk of developing a disorder which is characterized by reduced mitochondrial function, the method comprising determining if a gene from the subject contains a mutation which reduces the function of the gene, wherein the gene has an Errα
- binding site, a Gapba binding site, or both, wherein if a gene from the subject contains the mutation then the subject is at risk of developing the disorder.
- View Dependent Claims (48)
-
49-77. -77. (canceled)
-
78. A method of detecting statistically-significant differences in the expression level of at least one biomarker belonging to a biomarker set, between the members of a first and of a second experimental group, comprising:
-
(a) obtaining a biomarker sample from members of the first and the second experimental groups;
(b) determining, for each biomarker sample, the expression levels of at least one biomarker belonging to the biomarker set and of at least one biomarker not belonging to the set;
(c) generating a rank order of each biomarker according to a difference metric of its expression level in the first experimental group compared to the second experimental group;
(d) calculating an experimental enrichment score for the biomarker set by applying a non parametric statistic; and
(e) comparing the experimental enrichment score with a distribution of randomized enrichment scores to calculate the fraction of randomized enrichment scores greater than the experimental enrichment score, wherein a low fraction indicates a statistically-significant difference in the expression level of the biomarker set between the members of the first and of the second experimental group.
-
-
79-92. -92. (canceled)
-
93. A method of identifying an agent that regulates expression of OXPHOS-CR genes, the method comprising
(a) contacting (i) an agent to be assessed for its ability to regulate expression of OXPHOS-CR genes with (ii) a test cell; - and
(b) determining whether the expression of at least two OXPHOS-CR gene products show a coordinate change in the test cell compared to an appropriate control, wherein a coordinate change in the expression of the OXPHOS-CR gene products indicates that the agent regulates the expression of OXPHOS-CR genes.
- and
-
94-105. -105. (canceled)
Specification