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COL4A3 Variants and Susceptibility to Diabetic Nephropathy
Summary Data Summary
Applicant Miner, Jeffrey
E-Mail Address minerj@wustl.edu
Project Title COL4A3 Variants and Susceptibility to Diabetic Nephropathy
CBU ID 19AU4060
External SubContract ID 32307-63
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2019]
Abstract Diabetic nephropathy (DN) is a major diabetic complication that affects a large
fraction of both type I and II diabetic patients. One hallmark of DN is the
dramatic thickening of the glomerular basement membrane (GBM). The GBM is an
~300 nm-thick layer of extracellular matrix composed of many different proteins,
including collagen IV, laminin, nidogen, and heparan sulfate proteoglycan. It
has been assumed for decades that the GBM thickening observed in diabetic
nephropathy is directly related to the microalbuminuria and progression to frank
proteinuria that occurs in the fraction of type I and type II diabetic patients
who develop DN. Recently, Jose C. Florez of Harvard Medical School and
colleagues posted the results of a high-powered genome-wide association study
(GWAS) of diabetic kidney disease in type I patients. A non-synonymous variant
in COL4A3 (p.Asp326Tyr) was found to protect against the development of DN. Here
we propose to test the hypothesis that this COL4A3 variant results in a thinner
than normal GBM in healthy mice and will reduce the extent of GBM thickening and
diabetic nephropathy in type I diabetic mice. CRISPR/Cas9-mediated genome
editing will be used to introduce the human alleles into the mouse Col4a3 gene
in DBA/2J mice that have been shown to be susceptible to DN. Electron microscopy
will be used to quantify GBM width, and urine and blood will be analyzed to
determine whether the variant is protective. The results of these studies will
indicate whether or not the variant has a direct impact on GBM width and
severity of DN and whether modulation of GBM width should be viewed as a viable
target for therapy in patients. Diabetic nephropathy is a major cause of kidney
failure in the US, but there are no specific treatments to prevent it or stop
its progression. Here we will test whether a change to a protein that helps form
the kidney’s filtration barrier can protect from diabetic nephropathy in mice.
The results of these studies could lead to new treatment strategies for human
patients.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel Miner, Jeffrey
Salary Total Costs 35002
Supply Total Costs 12141
Equipment Total Costs 0
Travel/Other Total Costs 16500
Direct Costs 63643
Indirect Costs Proposed 36357
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 11/1/2019
End Date 10/31/2020
IFO Name Medley, Teri
IFO E-Mail Address researchgrants@wusm.wustl.edu
IACUC/IRB No. 20190043
IACUC/IRB Institution Washington University in St Louis
Entity ID No. A3381-01
Report Request Date 11/29/2020
T1D NO
TypeCount
Invoices 11
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  19AU406032307-63Washington University in St Louis9/5/2020$8,563.07$4,923.77$13,486.84$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis8/11/2020$4,715.11$2,711.19$7,426.30$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis7/11/2020$6,332.53$3,609.54$9,942.07$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis6/5/2020$4,518.93$2,575.79$7,094.72$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis5/7/2020$4,884.80$2,784.34$7,669.14$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis4/9/2020$7,434.22$4,237.51$11,671.73$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis3/6/2020$6,193.60$3,530.35$9,723.95$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis2/7/2020$4,048.30$2,307.53$6,355.83$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis12/6/2019$2,488.90$1,418.67$3,907.57$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis12/14/2020$5,431.92$3,123.35$8,555.27$6,007.48View PDF
  View  19AU406032307-63Washington University in St Louis10/9/2020$5,180.38$2,978.72$8,159.10$6,007.48View PDF


Reports
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