Medical Student Research Fellowship for Summer 2007
Mentor: Robert Toto
Department: Internal Medicine
Room number: H5.122
Mail Code: 8856
Phone number: 83442
Project title: Novel Biomarkers for Treatment Response in Diabetic Nephropathy
Human subjects IRB approved project number (where applicable):
Animal subjects IRB approved project number (where applicable): NA
Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Patient Based.
Brief Description of Project:
The broad, long-term objective of this project is to improve treatment of patients with chronic progressive kidney disease. The objective of this proposal is to obtain proof-of-principle data to determine whether urine proteome signatures from diabetics with nephropathy can predict the response to treatment with drugs that block renin-angiotensin system effector molecules, especially aldosterone. Both chip-based and novel proteomic methods will be applied to urine samples from participants in an ongoing NIHsponsored clinical trial in diabetics with nephropathy. The trial is designed to test the hypothesis that adding either an ARB or a mineralocorticoid receptor antagonist (MRA) to a maximally dosed ACEi-based regimen is superior to placebo for reducing urine albumin creatinine ratio, a standard marker of kidney
disease progression, by 30% after 12 months of treatment. We hypothesize that unique urine proteome signatures predict treatment response, defined as a 30% reduction in proteinuria, to chronic administration of either an angiotensin receptor blocker (ARB) or a mineralocorticoid antagonist (MRA) in diabetics with nephropathy on a maximally-dosed angiotensin converting enzyme inhibitor (ACEi). To test our hypothesis we propose the following specific aims:
1) Determine the reliability and stability of urine proteome: recruit 30 patients with diabetic nephropathy enrolled in our clinical trial and 30 age, gender and race-matched normal controls and obtain 3 consecutive daily urine samples for proteomic analysis; 2) Identify and validate potential biomarkers from urine proteome in diabetics with nephropathy: We will initially analyze 24-hour urine samples from 30 normal and 78 patients with diabetic nephropathy, enrolled in our ongoing clinical trial, with surfaceenhanced laser desorption-ionization time of flight (SELDI-TOF) mass spectrometry (MS) and by a novel two-dimensional chromatography separation method coupled with matrix-assisted desorption ionization-TOF high-resolution MS in order to identify potential biomarkers and 3) Identify and sequence novel protein biomarkers that signify treatment response to an ARB and an MRA in ACEi-treated diabetics with nephropathy. We will utilize banked urine samples collected at baseline, 24 and 48 weeks of administration of placebo or ARB or MRA added on to an ACE inhibitor in 78 diabetics participating in our prospective randomized double-blind placebo controlled trial. Biomarkers will be sequenced using high
resolution mass spectrometry. If successful we will analyze the proteome for markers that predict response to treatment with ARB or MRA. This project addresses a critical barrier in the field of diabetic nephropathy and represents a true collaboration between basic and clinical scientists. The availability of samples from a unique, well-characterized patient population and a team of investigators with experience, expertise, and proven track record is a powerful combination that should lead to improved understanding of diabetic nephropathy. Successful completion of these aims will lead to a future RO1 application to validate our findings in larger, external patient populations.
Previous Research Activities or Publications with Medical Students:
Michael Monaco worked on this project summer of 2006. He presented abstract
and poster in UTSW Med Stud Research forum January 2007
Vinu Ipe MS3 participated in this project and MSH study. He has a manuscript written that is ready to submit to JOI.
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