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Oxidative Stress, microRNA, and Hyper-Contractility in Diabetes
Summary Data Summary
Applicant Mahavadi, Sunila
E-Mail Address sunila.mahavadi@vcuhealth.org
Project Title Oxidative Stress, microRNA, and Hyper-Contractility in Diabetes
CBU ID 17AU3781
External SubContract ID 32307-4
Diabetic Complication Gastro-Intestinal (GI)
Funding Program Group Pilot & Feasibility [PF2017]
Abstract Impairment of gastrointestinal motility, such as delayed or rapid gastric
emptying, delayed intestinal transit, and constipation are prevalent in patients
with Type I and Type II diabetes and cause considerable morbidity. Numerous
studies have used animal models to show that depletion of enteric nNOS neurons
and interstitial cells of Cajal contributes to impairment of function. The
contribution of impaired smooth muscle function has not been explored. We have
obtained preliminary evidence that high glucose levels induce specific changes
in the expression of signaling targets (RGS4; CPI-17) mediating initial
Ca2+-dependent contraction and sustained Ca2+-independent contraction. The
changes augmented contraction in gastric smooth muscle from diabetic ob/ob mice
and in control smooth muscle treated for 48 h with high glucose. Downregulation
of RGS4 reduced inactivation of Gaq and augmented initial contraction.
Upregulation of CPI-17 increased inhibition of MLC phosphatase via the
PKC/CPI-17 pathways and augmented sustained contraction. We have now identified
two microRNAs (miRs) whose expression is driven by high glucose that
specifically regulate RGS4 (miR-1), and CPI-17 (miR-145) and have obtained
preliminary evidence that high levels of reactive oxygen species (ROS) generated
by increased glucose flux in mitochondria and via alternative glucose metabolic
pathways (glucosamine, polyol, and glyceraldehyde-3-P) mediate the changes in
miR expression, which, in turn, regulate the expression of signaling targets.
The effects of high glucose on (a) the expression of miRs and signaling targets,
(b) the activity of downstream effectors, and (c) the increase in contraction
were reversed by the antioxidant, N-acetyl cysteine. The Specific Aims of this
proposal are as follows: (1) Establish ROS as the link between high glucose
levels and microRNA regulators (miR-1, miR-145) of signaling targets (RGS4,
CPI-17) that mediate initial and sustained contraction in gastric smooth muscle
from ob/ob mice and in control smooth muscle treated with high glucose. (2)
Characterize the regulation of RGS4 expression by miR-1, and using selective
agomirs and antagomirs to define its contribution to changes in signaling via
the RGS4/Gaq/PLC-?1/IP3/Ca2+/MLC kinase/MLC20 cascade and CPI-17 expression by
miR-145 and define their contribution to signaling via the PKC/CPI-17/MLCP
pathways. The results from our studies have the potential to give novel insights
and strategies in the development and treatment of gastric motility dysfunction
in diabetes. These funds will be used to increase our understanding and develop
further focused extensive investigations utilizing NIH R01 funding.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 36391
Supply Total Costs 23000
Equipment Total Costs 0
Travel/Other Total Costs 5000
Direct Costs 64391
Indirect Costs Proposed 35415
Total Costs Proposed 99806
Total Costs Approved 99806
Start Date 11/1/2017
End Date 10/31/2018
IFO Name
IFO E-Mail Address
IACUC/IRB No. 9999
IACUC/IRB Institution Virginia Commonwealth University
Entity ID No.
Report Request Date 11/30/2018
T1D NO
TypeCount
Invoices 13
Progress Reports 2
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  17AU378132307-4Virginia Commonwealth University9/17/2018$5,553.62$3,054.49$8,608.11$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University8/13/2018$3,772.20$2,074.72$5,846.92$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University7/24/2018$7,207.48$3,964.12$11,171.60$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University6/7/2018$3,032.60$1,667.94$4,700.54$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University5/14/2018$1,516.30$833.97$2,350.27$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University4/5/2019$11,763.92$6,470.16$18,234.08$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University4/5/2018$4,548.92$2,501.91$7,050.83$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University3/19/2018$3,032.60$1,667.94$4,700.54$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University2/9/2018$7,905.21$4,347.87$12,253.08$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University2/6/2019$157.68$86.72$244.40$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University12/6/2018$2,290.21$1,259.62$3,549.83$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University11/12/2018$2,903.05$1,596.68$4,499.73$0.00View PDF
  View  17AU378132307-4Virginia Commonwealth University10/17/2018$10,707.14$5,888.93$16,596.07$0.00View PDF
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