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Testing a LOXL2 Inhibitor for Ameliorating Glomerulosclerosis in Diabetic Nephropathy
Summary Data Summary
Applicant Vanacore, Roberto
E-Mail Address roberto.vanacore@vanderbilt.edu
Project Title Testing a LOXL2 Inhibitor for Ameliorating Glomerulosclerosis in Diabetic
Nephropathy
CBU ID 16GRU3728
External SubContract ID 30835-20
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2016]
Abstract Diseases of the glomerulus, the filtering unit of the kidney, account for over
60% of all cases of end-stage renal disease (ESRD), a major health problem
worldwide. Diabetic nephropathy (DN) is the leading cause of ESRD. Despite
current treatments, the development and progression of nephropathy in the
patients with diabetes remains unpreventable. As many other progressive kidney
diseases, DN is characterized by thickening of glomerular and tubular basal
membranes, with progressive mesangial expansion and development of fibrosis.
Increased deposition of highly crosslinked collagen IV is known to be one of the
main component of fibrotic lesions. Interestingly, the expression of lysyl
oxidase like-2 (LOXL2), a member of the lysyl oxidase family, has been reported
to be upregulated in kidney biopsies of patients with chronic kidney disease,
including DN. We have recently demonstrated that LOXL2 is the main lysyl oxidase
isoform of glomerular basal membranes that crosslinks collagen IV. LOXL2 is
significantly upregulated in fibrotic glomeruli of diabetic eNOS -/- db/db mice,
a type II model of DN, which manifest characteristics reminiscent of type II
diabetes in humans. Preliminary studies in cultured podocytes and glomerular
endothelial cells suggest that LOXL2 upregulation is driven by TGF-ß
stimulation. With the intention to develop strategies that would reduce
glomerulosclerosis, we have identified a highly selective LOXL2 inhibitor that
efficiently inhibits LOXL2-mediated collagen IV crosslinking in a cell culture
system. Thus, we hypothesize that inhibition of LOXL2-mediated collagen IV
crosslinking will block or ameliorate the development of glomerulosclerosis in
diabetic animals. To test this hypothesis we have designed 3 specific aims. In
Aim 1 we will characterize LOXL2 during the course of DN development in eNOs -/-
db/db mice. Aim 2 will test the effectiveness of LOXL2 inhibitor (in combination
with angiotensin converting enzyme inhibitor (ACEI) or alone) to interfere with
glomerulosclerosis in DN animals. Aim 3 is designed to define the molecular
mechanisms by which LOXL2 is upregulated by TGF-b1 in glomerular cells. This
study would provide the first preclinical evidence for targeting LOXL2 to
improve DN therapies. Satisfactory results would be used to initiate funding
proposals to study the role of LOXL2 in glomerulosclerosis.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 20009
Supply Total Costs 15965
Equipment Total Costs 0
Travel/Other Total Costs 2000
Direct Costs 37974
Indirect Costs Proposed 22026
Total Costs Proposed 60000
Total Costs Approved 60000
Start Date 10/1/2016
End Date 9/30/2017
IFO Name Todd, Steve
IFO E-Mail Address steve.todd@vanderbilt.edu
IACUC/IRB No. 99999
IACUC/IRB Institution Vanderbilt University
Entity ID No. 35-2528741
Report Request Date 1/1/3000
T1D NO
TypeCount
Invoices 19
Progress Reports 0
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  16GRU372830835-20Vanderbilt University9/27/2017$6,334.01$3,673.73$10,007.74$4.12View PDF
  View  16GRU372830835-20Vanderbilt University8/8/2018$24.59$14.26$38.85$4.12View PDF
  View  16GRU372830835-20Vanderbilt University8/7/2017$2,618.15$1,518.53$4,136.68$4.12View PDF
  View  16GRU372830835-20Vanderbilt University7/18/2017$2,596.49$1,505.96$4,102.45$4.12View PDF
  View  16GRU372830835-20Vanderbilt University7/17/2018$106.63$61.85$168.48$4.12View PDF
  View  16GRU372830835-20Vanderbilt University6/7/2018$106.63$61.85$168.48$4.12View PDF
  View  16GRU372830835-20Vanderbilt University6/7/2017$2,328.29$1,350.41$3,678.70$4.12View PDF
  View  16GRU372830835-20Vanderbilt University5/7/2018$106.63$61.85$168.48$4.12View PDF
  View  16GRU372830835-20Vanderbilt University5/5/2017$2,280.89$1,322.92$3,603.81$4.12View PDF
  View  16GRU372830835-20Vanderbilt University4/9/2018$1,557.51$903.36$2,460.87$4.12View PDF
  View  16GRU372830835-20Vanderbilt University4/7/2017$720.81$418.07$1,138.88$4.12View PDF
  View  16GRU372830835-20Vanderbilt University3/8/2017$566.36$328.49$894.85$4.12View PDF
  View  16GRU372830835-20Vanderbilt University3/7/2018$1,459.83$846.70$2,306.53$4.12View PDF
  View  16GRU372830835-20Vanderbilt University2/8/2018$1,549.25$898.57$2,447.82$4.12View PDF
  View  16GRU372830835-20Vanderbilt University2/10/2017$521.86$302.68$824.54$4.12View PDF
  View  16GRU372830835-20Vanderbilt University12/7/2017$6,090.99$3,532.77$9,623.76$4.12View PDF
  View  16GRU372830835-20Vanderbilt University11/7/2017$3,299.76$1,913.86$5,213.62$4.12View PDF
  View  16GRU372830835-20Vanderbilt University10/6/2017$4,117.37$2,388.07$6,505.44$4.12View PDF
  View  16GRU372830835-20Vanderbilt University1/8/2018$1,586.01$919.89$2,505.90$4.12View PDF
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