p53-Regulated Metabolic Fitness of Self-Renewing Nephron Progenitor Cells
| Summary |
Data Summary |
| Investigator |
Saifudeen, Zubaida |
| Description |
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, variati
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| Status |
Completed |
| Public Release |
10/29/2017 |
| Data Collected? |
Data will not be collected for this catalog item |
| Species |
M. musculus |
| Animal Age |
Measured In: week(s) post-natal (w) |
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| Data Analysis |
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| Type | Count | Released |
| Animals | 0 | - |
| Experimental Conditions | 0 | - |
| Phenotype Assays | 0 | - |
| Phenotype Measurements | 0 | 0 |
| Microarrays | 0 | - |
| Histology Images | 0 | 0 |
| Publications | 0 | - |
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Experimental Factor Values