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Chromatin protein HMGB1 triggers endothelial dysfunction in diabetes via TLR4
Summary Data Summary
Applicant Webb, Clinton
E-Mail Address cwebb@augusta.edu
Project Title Chromatin protein HMGB1 triggers endothelial dysfunction in diabetes via TLR4
CBU ID 14GHSU1435
External SubContract ID NIDDK00056S3C
Diabetic Complication Uropathy
Funding Program Group Pilot & Feasibility [PF2014]
Abstract Diabetes mellitus (DM) is at epidemic levels in the U.S. and is a major cause of
cardiovascular disease. Endothelial dysfunction, a major contributor to the
onset of diabetic vascular complications, is characterized by diminished nitric
oxide (NO) bioavailability and increased generation of reactive oxygen species
(ROS), leading to impaired endothelium-dependent vasodilation, endothelial cell
(EC) apoptosis, and vascular inflammation. A critical barrier to improving
survival from DM is understanding how metabolic processes interface with immune
responses. The adaptive immune system is a contributing factor to the
development of DM; however, the mechanisms initiating the inflammatory response
is unknown. Damage-associated molecular patterns (DAMPs) are endogenous
molecules released by injured cells that impact the nature and magnitude of an
immune response by activating the innate immune system. High mobility group box
1 protein (HMGB1) is a DAMP released by necrotic cells that stimulates a
pro-inflammatory state via Toll-like receptors (TLR). The impact of HMGB1 on EC
function in DM is unknown. Based on our compelling preliminary data indicating
that TLR4 signaling is upregulated in the vasculature of diabetic animals and
its activation contributes to augmented ROS generation and impaired
vasodilation, our central hypothesis is that HMGB1 activates TLR4 signaling in
EC leading to endothelial dysfunction. Two specific aims are proposed: 1) To
test the hypothesis that HMGB1 activates TLR4 signaling in human aortic EC
leading to increased ROS generation, decreased NO bioavailability and NFKB
activation, which will result in in EC apoptosis and inflammation. 2) To test
the hypothesis that HMGB1 induces impaired endothelium-dependent vasodilatation
in DM through mechanisms that involve TLR4. Streptozotocin will be used to
induce diabetes in C57Bl/6 and TLR4-/- mice. Some mice will be treated with an
anti-HMGB1 neutralizing antibody. Endothelium-dependent relaxation will be
measured in isolated aortic rings. Elucidation of the role for HMGB1 in diabetic
endothelial dysfunction has the potential to shed new insight into the
development of therapeutic strategies for prevention or intervention of this
disorder.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 52879
Supply Total Costs 34830
Equipment Total Costs 0
Travel/Other Total Costs 3200
Direct Costs 90909
Indirect Costs Proposed 9091
Total Costs Proposed 100000
Total Costs Approved 100000
Start Date 10/1/2014
End Date 9/30/2015
IFO Name White, Sarah
IFO E-Mail Address ogc@augusta.edu
IACUC/IRB No. N/A
IACUC/IRB Institution Georgia Regents University
Entity ID No. 1-58-1418202-A1
Report Request Date 10/30/2015
T1D NO
TypeCount
Invoices 0
Progress Reports 1
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