Computational knowledge model to discover molecular causes and treatment of diabetes mellitus
In one aspect, the invention comprises a method of developing an immunosuppressant drug with reduced propensity to induce type II diabetes mellitus symptoms by assaying candidate molecular entities for binding preferentially to leukocyte isoform calcineurin and less preferentially to muscle cell isoform calcineurin. In another aspect, the invention comprises a method for determining the onset, severity, or response to treatment of post-transplant diabetes mellitus comprising determining from a patient at risk of contracting post-transplant diabetes mellitus, at least two of increased expression of HDAC5 protein; increased expression of HNF4A protein; decreased expression of NRF1 protein; decreased expression of PPARGC1 protein; and decreased expression of PPP3CA protein.
1 . A method of developing an immunosuppressant drug with reduced propensity to induce type II diabetes symptoms, the method comprising:
assaying candidate molecular entities for binding preferentially to leukocyte isoform calcineurin and less preferentially to muscle cell isoform calcineurin.
2 . The method of claim 1 wherein the candidate molecular entities comprise molecules adjacent in chemical space to FK506 or a cyclosporine.
3 . The method of claim 1 wherein the binding assay is conducted using immobilized calcineurin isoforms or labeled soluble calcineurin isoforms.
4 . The method of claim 1 wherein the leukocyte isoform calcineurin is a calcineurin dimer.
5 . The method of claim 1 wherein the muscle cell isoform calcineurin is a calcineurin dimer.
6 . The method of claim 1 wherein the leukocyte isoform calcineurin and the muscle cell isoform calcineurin are splice variants of each other.
7 . A method for determining the onset, severity, progression or response to treatment of post-transplant diabetes mellitus comprising determining from a patient at risk of contracting post-transplant diabetes mellitus, at least two of:
increased expression or activity of HDAC5 protein;
increased expression or activity of HNF4A protein;
decreased expression or activity of NRF1 protein;
decreased expression or activity of PPARGC1 protein;
decreased expression or activity of PPP3CA protein; and
decreased expression or activity of calcineurin proteins.
8 . The method of claim 7 comprising determining decreased expression or activity of PPARGC1 protein.
9 . The method of claim 7 comprising assaying for protein concentrations or activity in a muscle cell from a muscle biopsy from a said patient.
10 . The method of claim 7 comprising assaying for gene transcripts or biomolecules produced by interaction with a said protein as a proxy for an increase or decrease in said protein expression or activity.