A Metabolomic Approach to Discovering Biomarkers for ADPKD

Summary

Principal Investigator: R H Weiss
Abstract: DESCRIPTION (provided by applicant): ADPKD is the most prevalent inherited renal disease, accounting for 4% of the ESRD population. Detection of renal cysts utilizing renal imaging has been the most common method of diagnosis of this disease however, cyst appearance is often delayed with affected individuals not demonstrating renal cystic disease until the 4th decade of life. At present, other than genotyping, there is no test to diagnose the disease in its earliest stages and is successful only 85% of the time. In this revised proposal, we will exploit the new science of metabolomics, in collaboration with internationally-renowned experts in this nascent field, to discover a pattern of urinary and plasma metabolites which serve as biomarkers for ADPKD. We will utilize patient materials from the ongoing HALT study;a HALT Principal Investigator is the co-Investigator for this study. Our collaborating biostatistician has calculated the desired sample size utilizing preliminary data derived from preliminary urinary metabolomic analysis of patients and controls from our two institutions. Our proposal is extraordinary in that we have assembled a unique cadre of investigators: a cell biologist who is also a clinician-scientist nephrologist (Dr. Weiss), a nephrologist and clinical trials expert (Dr. Chapman), a proteomics and genomics bioinformatics expert (Dr. Perroud), four metabolomics experts (Drs Hammock, Grant, Michelmore and Fiehn), and a biostatistician with expertise in "omic" analyses (Dr. Kim) to utilize metabolomics to tackle the problem of diagnosis and treatment of a relatively common disease which is difficult to diagnose, and for which current treatment options are limited. The application has been markedly improved since the original submission by the addition of more preliminary data (including a human control trial and a mouse PKD metabolomic experiment), as well as narrative which addresses all of the concerns of the original reviewers including a new Specific Aim which addresses important concerns about control data interpretation. Several additional metabolomics experts at the PI's institution, with whom he has ongoing scientific relationships, have been recruited for this revision to assist in complicated metabolomic data interpretation, should this become necessary. Successful completion of these experiments will result in a major advance in diagnosis as well as, ultimately, the selection of optimal treatment regimens for this disease. Ours will be the first described use of metabolomics in cystic kidney disease, and one of the first to exploit this technology in any renal disease. Furthermore, our work can serve as a model for using metabolomics to glean pathway and network data from a variety of hereditary diseases. PUBLIC HEALTH RELEVANCE: NARRATIVE ADPKD is the most prevalent inherited renal disease accounting for 4% of the ESRD population. At present, other than genotyping, which is successful only 85% of the time, there is no test to diagnose the disease in its early, pre-cystic stages at which time novel therapies have the best chance of being effective. This project will lead to a simple, office-based urine and/or blood test for detection of ADPKD, which can be utilized in the primary care, nephrology, and urology clinics and which will lead to earlier treatment of this relatively common disease. In addition, work from this proposal will lead to new knowledge about the pathology of the disease and to selection of patients who will most benefit from any new drug.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB
    Aaron T Wecksler
    Departments of aEntomology and Nematology bNeurobiology, Physiology and Behavior, University of California Davis, Davis cUC Davis Comprehensive Cancer Center dDepartment of Internal Medicine, Davis Medical Center, Division of Nephrology, University of California eDepartment of Biochemistry and Molecular Medicine, University of California Davis School of Medicine fUS Department of Veterans Affairs Medical Center, Sacramento, California, USA
    Anticancer Drugs 25:433-46. 2014
  2. pmc Mealtime, temporal, and daily variability of the human urinary and plasma metabolomes in a tightly controlled environment
    Kyoungmi Kim
    Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Davis, California, United States of America
    PLoS ONE 9:e86223. 2014
  3. pmc Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells
    Omran Abu Aboud
    Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, California, United States of America
    PLoS ONE 8:e71115. 2013
  4. pmc Stability of miRNA in human urine supports its biomarker potential
    Christine Mall
    Division of Nephrology, Department of Internal Medicine, Genome and Biomedical Sciences Building, Room 6312, University of California, Davis, CA 95616, USA
    Biomark Med 7:623-31. 2013
  5. pmc Anti-inflammatory effects of ω-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension
    Arzu Ulu
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA
    J Cardiovasc Pharmacol 62:285-97. 2013
  6. pmc Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
    Guodong Zhang
    Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:6530-5. 2013
  7. ncbi Potential biofluid markers and treatment targets for renal cell carcinoma
    Hiromi I Wettersten
    Division of Nephrology, University of California, Davis, CA 95616, USA
    Nat Rev Urol 10:336-44. 2013
  8. pmc Applications of metabolomics for kidney disease research: from biomarkers to therapeutic targets
    Hiromi I Wettersten
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA, USA
    Organogenesis 9:11-8. 2013
  9. pmc A novel p21 attenuator which is structurally related to sorafenib
    Hiromi I Wettersten
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA
    Cancer Biol Ther 14:278-85. 2013
  10. ncbi New opportunities from the cancer metabolome
    Omran Abu Aboud
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA, USA
    Clin Chem 59:138-46. 2013

Scientific Experts

  • Mathias Lichterfeld
  • Robert H Weiss
  • Hiromi I Wettersten
  • Sheila Ganti
  • Kyoungmi Kim
  • Sandra L Taylor
  • Bruce D Hammock
  • Omran Abu Aboud
  • Hiromi Inoue
  • Aaron T Wecksler
  • Sung Hee Hwang
  • Christine Mall
  • Arzu Ulu
  • Joy Yang
  • Jun Yan Liu
  • Guodong Zhang
  • Arlene Chapman
  • Christopher Evans
  • Michael V Osier
  • Lining Guo
  • Xu G Yu
  • Florencia Pereyra
  • Katherine Seiss
  • Abraham L Brass
  • Huabiao Chen
  • Eric S Rosenberg
  • Maria J Buzon
  • Aldrin V Gomes
  • Chen Zhang
  • Amy Patton
  • Keith Baar
  • Kermit L Carraway
  • A Daniel Jones
  • Jennifer E Gilda
  • Leonardo J Leon
  • Stacie Hitchcock
  • Eunice Y Shiu
  • Michael Kauffman
  • Christina Miyabe
  • Dipak Panigrahy
  • Sarah Tam
  • Jun Yang
  • Yosef Landesman
  • Nipavan Chiamvimonvat
  • David M Rocke
  • Blythe Durbin-Johnson
  • Christopher P Evans
  • Katherine W Ferrara
  • Cuiwen Li
  • John D Imig
  • Christophe Morisseau
  • Sharon Shacham
  • Lisa M Mahakian
  • Ana Maria Iosif
  • Xiaowen Hu
  • Gertrud Schuster
  • Hua Dong
  • Mark W Kieran
  • Elizabeth S Ingham
  • Kin Sing Stephen Lee
  • Todd R Harris
  • Charles L Hoppel
  • Danny C Alexander
  • Thai Cung
  • Yue Yang
  • Jinghe Huang
  • Jill Beamon
  • Lindsay C Porter
  • Mary F Carrington
  • Bethany J Ryan
  • Patrick S Burke
  • WILLIAM D CRESS
  • Bruce D Walker
  • Robert Weiss
  • Chun Li
  • Ruiwu Liu
  • Nikolay O Bukanov
  • Michael Osier
  • Oliver Fiehn

Detail Information

Publications19

  1. pmc Novel sorafenib-based structural analogues: in-vitro anticancer evaluation of t-MTUCB and t-AUCMB
    Aaron T Wecksler
    Departments of aEntomology and Nematology bNeurobiology, Physiology and Behavior, University of California Davis, Davis cUC Davis Comprehensive Cancer Center dDepartment of Internal Medicine, Davis Medical Center, Division of Nephrology, University of California eDepartment of Biochemistry and Molecular Medicine, University of California Davis School of Medicine fUS Department of Veterans Affairs Medical Center, Sacramento, California, USA
    Anticancer Drugs 25:433-46. 2014
    ....
  2. pmc Mealtime, temporal, and daily variability of the human urinary and plasma metabolomes in a tightly controlled environment
    Kyoungmi Kim
    Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, Davis, California, United States of America
    PLoS ONE 9:e86223. 2014
    ..In light of these findings, future metabolomics studies should consider these sources of variability to allow for appropriate metabolomics testing and reliable clinical translation of metabolomics data. ..
  3. pmc Inhibition of PPARα induces cell cycle arrest and apoptosis, and synergizes with glycolysis inhibition in kidney cancer cells
    Omran Abu Aboud
    Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, California, United States of America
    PLoS ONE 8:e71115. 2013
    ....
  4. pmc Stability of miRNA in human urine supports its biomarker potential
    Christine Mall
    Division of Nephrology, Department of Internal Medicine, Genome and Biomedical Sciences Building, Room 6312, University of California, Davis, CA 95616, USA
    Biomark Med 7:623-31. 2013
    ..miRNAs are showing utility as biomarkers in urologic disease, however, a rigorous evaluation of their stability in urine is lacking. Here, we evaluate the stability of miRNAs in urine under clinically relevant storage procedures...
  5. pmc Anti-inflammatory effects of ω-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension
    Arzu Ulu
    Department of Entomology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA
    J Cardiovasc Pharmacol 62:285-97. 2013
    ....
  6. pmc Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis
    Guodong Zhang
    Department of Entomology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:6530-5. 2013
    ..These results designate epoxyeicosatrienoic acids and EDPs as unique endogenous mediators of an angiogenic switch to regulate tumorigenesis and implicate a unique mechanistic linkage between omega-3 and omega-6 fatty acids and cancers...
  7. ncbi Potential biofluid markers and treatment targets for renal cell carcinoma
    Hiromi I Wettersten
    Division of Nephrology, University of California, Davis, CA 95616, USA
    Nat Rev Urol 10:336-44. 2013
    ..Many promising leads for new targeted therapies have come to light; some of these therapies are in clinical trials and others are still being evaluated in the laboratory...
  8. pmc Applications of metabolomics for kidney disease research: from biomarkers to therapeutic targets
    Hiromi I Wettersten
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA, USA
    Organogenesis 9:11-8. 2013
    ..It is quite likely that, with greater numbers of clinical materials and with more investigators jumping into the field, metabolomics may well change the course of kidney disease research. ..
  9. pmc A novel p21 attenuator which is structurally related to sorafenib
    Hiromi I Wettersten
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, Davis, CA, USA
    Cancer Biol Ther 14:278-85. 2013
    ..Thus, this novel p21 inhibitor will be indispensable for exploring the function of p21, and upon further study may be translatable to the clinic...
  10. ncbi New opportunities from the cancer metabolome
    Omran Abu Aboud
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA, USA
    Clin Chem 59:138-46. 2013
    ..Metabolomics has a great and largely untapped potential in the field of oncology, and the analysis of the cancer metabolome to identify biofluid markers and novel druggable targets can now be undertaken in many research laboratories...
  11. ncbi CRM1 blockade by selective inhibitors of nuclear export attenuates kidney cancer growth
    Hiromi Inoue
    Division of Nephrology, Department of Internal Medicine, University of California Davis, Davis, California 95616, USA
    J Urol 189:2317-26. 2013
    ..We identified and evaluated the nuclear exporter protein CRM1 as a novel potential therapy for renal cell carcinoma...
  12. pmc Kidney tumor biomarkers revealed by simultaneous multiple matrix metabolomics analysis
    Sheila Ganti
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, California 95616, USA
    Cancer Res 72:3471-9. 2012
    ....
  13. pmc Urine metabolomics for kidney cancer detection and biomarker discovery
    Sheila Ganti
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616, USA
    Urol Oncol 29:551-7. 2011
    ..The objective of this review is to discuss existing methods for sample collection, processing, data analysis, and recent findings in this emerging field...
  14. pmc Sorafenib attenuates p21 in kidney cancer cells and augments cell death in combination with DNA-damaging chemotherapy
    Hiromi Inoue
    Division of Nephrology Department of Internal Medicine, University of California, Davis, CA, USA
    Cancer Biol Ther 12:827-36. 2011
    ....
  15. pmc Inhibition of HIV-1 integration in ex vivo-infected CD4 T cells from elite controllers
    Maria J Buzon
    Infectious Disease Division, Massachusetts General Hospital, Boston, MA 02114
    J Virol 85:9646-50. 2011
    ..These data contribute to increasing evidence that intrinsic inhibition of specific HIV-1 replication steps plays an important role in the ability of elite controllers to maintain undetectable viral loads...
  16. pmc Urinary acylcarnitines are altered in human kidney cancer
    Sheila Ganti
    Division of Nephrology, Department of Internal Medicine, University of California, Davis, CA 95616, USA
    Int J Cancer 130:2791-800. 2012
    ..Furthermore, these findings open up a new area of investigation into the metabolic basis of kidney cancer...
  17. pmc CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21
    Huabiao Chen
    Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, Massachusetts, USA
    J Clin Invest 121:1549-60. 2011
    ..These data demonstrate a mechanism of host resistance to HIV-1 in elite controllers and may open novel perspectives for clinical strategies to prevent or treat HIV-1 infection...
  18. pmc Urine metabolomic analysis identifies potential biomarkers and pathogenic pathways in kidney cancer
    Kyoungmi Kim
    Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, California 95616, USA
    OMICS 15:293-303. 2011
    ..Further evaluation of the global metabolomics analysis, as well as confirmation of the specific potential biomarkers using a larger sample size, will lead to new avenues of kidney cancer diagnosis and therapy...
  19. pmc A metabolomics approach using juvenile cystic mice to identify urinary biomarkers and altered pathways in polycystic kidney disease
    Sandra L Taylor
    Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, CA 95616, USA
    Am J Physiol Renal Physiol 298:F909-22. 2010
    ..Thus, urine metabolomics has great diagnostic potential for cystic renal disorders and deserves further study...