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Molecular and pathological signature of the human kidney tubule in progression of diabetic nephropathy.
Summary Data Summary
Applicant Dagher, Pierre
E-Mail Address pdaghe2@iu.edu
Project Title Molecular and pathological signature of the human kidney tubule in progression
of diabetic nephropathy.
CBU ID 16GRU3669
External SubContract ID 30835-2
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2016]
Abstract There is a fundamental gap in understanding the mechanisms that determine
disease progression in human diabetic nephropathy (DN). Continued existence of
this gap presents an important clinical problem because specific therapeutic
interventions to treat or slow disease progression cannot be fully realized
until this gap is filled. The long term goal is to characterize key cellular and
molecular pathways regulating progression of DN, to identify novel markers that
assess disease progression, and to develop specific therapeutic interventions
targeting these pathways. The cross-talk between tubular subsegments and immune
cells in the kidney is an important determinant of fibrosis and disease
progression in DN. Consequently, the objective of this application is to
selectively examine the transcriptome of tubular subsegments and to quantify and
localize immune cell subtypes in relation to tubular subsegments in patients
with DN. The central hypothesis of this application is that the transcriptome of
kidney tubular subsegments and the abundance and distribution of immune cell
subtypes are unique and complimentary identifiers of disease progression in
human DN. This hypothesis has been formulated on the basis of existing
literature and strong preliminary data from the applicants’ laboratories. The
rationale for the proposed research is that once the unique molecular and
cellular identifiers that correlate with disease progression and long term
outcomes in DN are determined, they can be used to monitor efficacy of
pharmacologic interventions, identify animal models that best represent human DN
for translational research, and reveal novel pharmacological approaches towards
treating human DN. The central hypothesis will be tested by pursuing two
specific aims: 1) Define the transcriptome expressed by the tubular subsegments
from biopsies of patients with diabetic nephropathy and different rates of
progression and 2) Determine the abundance and distribution of immune cell
subtypes in the same set of patient biopsies. Under the first aim, laser
microdissection of tubular subsegments will be performed on biobanked kidney
biopsies from case-matched patients with DN that rapidly progressed (decrease in
eGFR > 5 mL/min/1.73m2/year) and those that did not rapidly progress (decrease
in eGFR < 5 mL/min/1.73m2/year). Gene expression analysis will be performed on
RNA isolated from the tubular subsegments utilizing solid-state transcriptome
array chips to discern the transcriptomic signature of the isolated tubular
subsegments. Under the second aim, advanced three-dimensional (3-D) tissue
cytometry will be performed on the biobanked kidney biopsies from the same
case-matched patients described in the first aim to quantify the immune cell
composition, examine spatial cellular organization, and delineate detailed
morphologic differences in patients with DN that rapidly progressed and those
that did not rapidly progress. The approach is innovative, because it represents
a new and substantive advancement in the molecular and morphological
interrogation of human kidney biopsies, namely characterization of the
transcriptomic signature of tubular subsegments in individual human kidney
biopsies combined with unique 3D cytometric analysis of the same biopsies. The
proposed research is significant, because it is the next step in a continuum of
research that is expected to identify critically needed biomarkers of disease
progression, optimize preclinical studies, and develop specific and targeted
therapeutic interventions in the vast clinical problem of DN.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 9131
Supply Total Costs 44372
Equipment Total Costs 0
Travel/Other Total Costs 10600
Direct Costs 64103
Indirect Costs Proposed 35897
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 10/1/2016
End Date 9/30/2017
IFO Name Becker, James
IFO E-Mail Address spon2@iupui.edu
IACUC/IRB No. 1601431846
IACUC/IRB Institution Indiana University - Indianapolis
Entity ID No. 1-35-6001673-A1
Report Request Date 11/30/2017
T1D NO
TypeCount
Invoices 10
Progress Reports 2
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  16GRU366930835-2Indiana University - Indianapolis9/25/2017$2,666.45$1,493.14$4,159.59-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis7/25/2017$969.55$542.85$1,512.40-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis6/23/2017$1,006.81$563.69$1,570.50-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis5/16/2017$1,029.55$576.45$1,606.00-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis4/21/2017$2,373.51$1,329.05$3,702.56-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis3/14/2017$2,495.25$1,397.23$3,892.48-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis2/6/2017$2,073.16$1,160.79$3,233.95-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis12/15/2017$47,515.75$26,609.02$74,124.77-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis11/27/2017$1,111.00$622.14$1,733.14-View PDF
  View  16GRU366930835-2Indiana University - Indianapolis10/31/2017$2,861.97$1,602.64$4,464.61-View PDF
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