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p53-Regulated Metabolic Fitness of Self-Renewing Nephron Progenitor Cells
Summary Data Summary
Applicant Saifudeen, Zubaida
E-Mail Address zubisaif@tulane.edu
Project Title p53-Regulated Metabolic Fitness of Self-Renewing Nephron Progenitor Cells
CBU ID 14GHSU1416
External SubContract ID 25034-54
Diabetic Complication Nephropathy
Funding Program Group Pilot & Feasibility [PF2014]
Abstract Nearly 3-10% of all pregnancies are affected by abnormal glucose regulation.
Infants of diabetic mothers (IDM) are at a four-fold higher risk for congenital
malformations of kidneys, brain and heart, as well as antenatal, perinatal or
neonatal morbidity. Renal defects include hypoplasia with a significant nephron
deficit, agenesis, cystic kidneys, ureteral duplication and hydronephrosis.
Congenital low nephron number is a common cause of pediatric renal failure,
adult-onset hypertension and chronic kidney disease - all clinically significant
diseases without a cure. Availability of nephron progenitor cells (NPC) and
their efficient differentiation into nephrons are major determinants of nephron
endowment. The Cited1+/Six2+ sub-compartment of the cap mesenchyme is the stem
cell niche, and marks the definitive self-renewing NPC. A self-renewal defect
would result in a loss of these cells and consequently a diminished progenitor
pool. A fundamental question is what regulates the stemness of NPCs. In a
conditional knock-out model of the transcription factor p53 from the nephron
progenitor cells, we observed progressive and selective depletion of
self-renewing progenitors, nephron deficit and adult-onset hypertension. RNA-Seq
data indicate that top down-regulated genes regulate energy metabolism pathways.
Preliminary mechanistic studies demonstrate decreased ATP and ROS levels in
Six2p53-/- cells. Balanced ATP and biomass synthesis (nucleotides, amino acids
etc.) via oxidative phosphorylation (Oxphos) and glycolysis, respectively, are
critical drivers of self-renewal and proliferation. Cell competition studies in
Drosophila implicate p53 as a sensor and key modulator of adaptive metabolic
changes to maintain cell viability. Based on these data we hypothesize that p53
enables self-renewal of the NPC by maintaining metabolic homeostasis in response
to niche cues. Our long-term goal is to define the role of p53 in integrating
niche signals (nutrient, growth factors, variations in oxygen tension) with key
sensory pathways (AMPK, mTOR, Hif1a). For this pilot study we propose to
establish the metabolic profile of Cited1+/Six2+ cells, which is currently
unknown, under normal, high and low glucose conditions, and evaluate
Cited1+/Six2+ NPC cell fate after a metabolic switch (by pharmacological
inhibition of glycolysis or Oxphos.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 28703
Supply Total Costs 30000
Equipment Total Costs 0
Travel/Other Total Costs 4500
Direct Costs 63203
Indirect Costs Proposed 31918
Total Costs Proposed 95121
Total Costs Approved 95121
Start Date 10/1/2014
End Date 9/30/2015
IFO Name Kozar, Kathleen
IFO E-Mail Address elecnotf@tulane.edu
IACUC/IRB No. A4499-01
IACUC/IRB Institution Tulane University Health Sciences Center Campus
Entity ID No. 72-0423889
Report Request Date 10/30/2015
T1D NO
TypeCount
Invoices 11
Progress Reports 1
Experiments 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus9/14/2015$11,366.99-$11,366.99-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus8/12/2015$7,507.21-$7,507.21-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus7/23/2015$14,309.59-$14,309.59-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus6/10/2015$5,867.71-$5,867.71-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus5/12/2015$6,848.50-$6,848.50-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus4/13/2015$7,256.78-$7,256.78-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus3/10/2015$5,672.36-$5,672.36-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus2/10/2015$18,584.76-$18,584.76-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus12/10/2014$5,643.33-$5,643.33-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus11/12/2014$2,331.08-$2,331.08-View PDF
  View  14GHSU141625034-54Tulane University Health Sciences Center Campus11/10/2015$9,732.69-$9,732.69-View PDF


Experiments
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