Medical Student Research Fellowship for Summer 2007
Mentor: Robert Toto
Department: Internal Medicine
Room number: H5.122
Mail Code: 8856
Phone number: 83442
E-mail: Robert.totoo@utsouthwestern.edu
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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