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Genetic Model for Bladder Dysfunction in Type 2 Diabetes
Summary Data Summary
Applicant Olumi, Aria
E-Mail Address aolumi@bidmc.harvard.edu
Project Title Genetic Model for Bladder Dysfunction in Type 2 Diabetes
CBU ID 09MCG72
External SubContract ID 23789-9
Diabetic Complication Uropathy
Funding Program Group Pilot & Feasibility [PF2009]
Abstract Type 2 diabetes mellitus (DM2) stems from insulin resistance and affects 7% of
the US population. Lower urinary tract dysfunction is one of the major urologic
complications associated with DM2, and the patients present with detrusor
overactivity or underactivity. Although diabetic bladder dysfunction affects up
to 80% of patients with DM2 its underlying pathophysiology is poorly understood.
Here, we demonstrate a genetic mouse model with DM2 with conditional knockout of
insulin receptor substrates 1 & 2 (Irs1, Irs2), which mimic the diabetic lower
urinary tract dysfunction in humans.

The DKO (Irs1, Irs2) organ-specific (hepatocyte) conditional knockout animal
system is a powerful model for DM2 which demonstrates the secondary bladder
cystopathy observed in humans. As opposed to many previous animal models that
have utilized the streptozotocin system, which more closely resembles type 1
diabetes, the DKO model is associated with insulin resistance which resembles
DM2. In addition, the DKO mice are not obese, therefore, uncoupling DM2 from
obesity. The DM2 in the DKO model is reversed in the TKO model (Irs1, Irs2 &
Foxo1 knockout), enabling us to examine fundamental questions associated with
correction of DM2 and bladder dysfunction and the molecular mechanisms that may
be responsible for the compensated and decompensated states of diabetic
cystopathy. We hypothesize that the phosphorylated myosin light chain (pMLC) is
a key regulator of the compensated and decompensated states of diabetic
cystopathy.

Specific Aim 1: To determine if correction of DM2 in a genetic animal model will
restore the bladder function. The DKO mice develop hyperglycemia and
dyslipidemia the fifth week of life and the metabolic abnormalities last beyond
30 weeks of life. The metabolic dysregulation of DM2 in DKO mice is reversed by
inhibition of the FOXO1 gene, therefore, we will determine whether the bladder
dysfunction and altered expression of pMLC that is observed in the DKO is
reversible and age-dependent.

Specific Aim 2: To determine the effect of high-glucose concentration on
inflammatory mediators in DKO mice. Hyperglycemia secondary to insulin
resistance is one of the hallmarks of DM2. One of the key associated findings
with hyperglycemia is hyper-glucosuria which can significantly affect a DM2
patient’s lower urinary tract symptoms. However, the molecular alterations
associated with hyper-glucosuria are not well understood. Here we will
investigate the effect of high glucose concentration on inflammatory modulators,
TNFa and IL-6, and examine how they may regulate the phosphorylated myosin light
chain (pMLC) in the bladder smooth muscle of DKO mice.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 38346
Supply Total Costs 21654
Equipment Total Costs 0
Travel/Other Total Costs 0
Direct Costs 60000
Indirect Costs Proposed 0
Total Costs Proposed 60000
Total Costs Approved 63000
Start Date 9/1/2009
End Date 8/31/2011
IFO Name Seger, Robert
IFO E-Mail Address rseger@partners.org
IACUC/IRB No. A3596-01
IACUC/IRB Institution Massachusetts General Hospital
Entity ID No. 1042697983A1
Report Request Date 9/30/2010
T1D NO
TypeCount
Invoices 0
Progress Reports 1
Data Submission


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