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Mechanisms of Glomerular Hypercellularity in Diabetic Nephropathy
Summary Data Summary
Applicant KELLY, K.J.
E-Mail Address kajkelly@iu.edu
Project Title Mechanisms of Glomerular Hypercellularity in Diabetic Nephropathy
CBU ID 19AU4057
External SubContract ID 32307-60
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2019]
Abstract There is a critical need for a better understanding of the pathophysiology of
diabetic nephropathy (DN). Continued existence of this fundamental knowledge 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 of this research is to characterize
key cellular and molecular pathways regulating DN and its progression in order
to identify novel markers that assess disease progression, and to develop
specific therapeutic interventions targeting these pathways. Accumulating
evidence points to the importance of tubular injury in the pathogenesis of DN
and other glomerular diseases. In addition, there is evidence in animal models
that proximal tubule cells can affect the glomerular compartment. We hypothesize
that growth factors derived from proximal tubules affect glomerular cellularity.
Consequently, the objectives of this application are to characterize the
increased cellularity found in glomeruli of human diabetic biopsies and examine
the transcriptome of proximal tubules and glomeruli to quantify trophic factors
and other pathways that account for the increased glomerular cellularity. The
central hypothesis of this application is that the transcriptome of the proximal
tubule predicts the glomerular cellularity which is a unique indicator of DN.
This hypothesis has been formulated on the basis of existing literature and
strong preliminary data from the applicant’s laboratory. The rationale for the
proposed research is that once the unique molecular and cellular identifiers of
human 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) Characterize the cellularity in glomeruli from human diabetic
biopsies and 2) Define the transcriptome of the same glomeruli and the adjacent
S1/S2 proximal tubule segments in the same set of patient biopsies. The
transcriptomes will be correlated with the cell types found in aim 1. In aim 1,
advanced three-dimensional tissue cytometry will be performed on bio-banked
kidney biopsies from patients with diabetic nephropathy in order to quantify the
cellular composition of the glomeruli. In aim 2, laser microdissection of the
same glomeruli and proximal tubule sub segments on the DN biopsies. Gene
expression analysis will be performed on RNA isolated from the proximal tubules
and glomeruli utilizing solid-state transcriptome array chips to discern the
transcriptomic signature of the isolated renal compartments. The transcriptomes
will be correlated with the cellularity and specific cell types in DN glomeruli.
The approach is innovative, because it represents a new and substantive
advancement in the molecular and morphological interrogation of human kidney
biopsies, namely a unique 3D cytometric analysis of diabetic glomeruli as well
as characterization and of the transcriptomic signature of proximal tubules and
glomeruli in individual human kidney 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 K.J. Kelly
Tarek Ashkar
Pierre Dagher
Jesus Dominguez
Kenneth Dunn
Michael Eadon
Carrie Phillips
Timothy Sutton
Salary Total Costs 41433
Supply Total Costs 4059
Equipment Total Costs 0
Travel/Other Total Costs 18000
Direct Costs 63492
Indirect Costs Proposed 36508
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 11/1/2019
End Date 6/30/2023
IFO Name Becker, James
IFO E-Mail Address jambecke@iu.edu
IACUC/IRB No. 1601431846
IACUC/IRB Institution Indiana University-Purdue University-Indianapolis
Entity ID No. 1-35-6001673-A1
Report Request Date 6/30/2023
T1D NO
TypeCount
Invoices 8
Progress Reports 2
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis8/22/2023$15,282.07$8,787.19$24,069.26$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis7/27/2020$11,972.88$6,884.40$18,857.28$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis6/6/2023$6,223.55$3,418.05$9,641.60$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis4/10/2020$9,638.50$5,542.13$15,180.63$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis3/9/2023$2,161.68$1,242.96$3,404.64$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis12/16/2020$2,191.96$1,260.38$3,452.34$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis12/10/2019---$15,587.71View PDF
  View  19AU405732307-60Indiana University-Purdue University-Indianapolis10/16/2020$6,226.38$3,580.16$9,806.54$15,587.71View PDF
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