? Diabetes mellitus (DM) is a common disorder and has a worldwide prevalence of 5-6% (1). DM is the fourth leading cause of death by disease and nearly 20 million Americans have this disease. Gastrointestinal dysfunction may occur in as many as 75% of diabetic patients. Current treatment options for diabetic gastrointestinal complications are limited to include drugs that stimulate gastrointestinal motility (1). Therefore, it is important to elucidate pathological changes in the enteric neurons affected by DM and the pathophysiological mechanisms of neuronal injury. We have previously shown that DM is associated with an increase in enteric neuronal apoptosis and loss of nNOS containing enteric neurons both in vitro and in vivo (2). The loss of enteric neurons plays an important role in the pathogenesis of diabetic neuropathy. Preliminary data shows that the loss of these neurons may be secondary to increased oxidative stress. NF?B has been implicated in the pathogenesis of diabetic neuropathy, and oxidative stress can trigger the activation of NFKB through several mechanisms. One of the mechanisms that reactive oxygen species can trigger activation of NFKB is through activation of the surface Toll like receptors (TLRs) which in turn trigger signaling events that degrade IKB and activate NFKB (3). To determine if TLRs have a role in modulating enteric neuronal survival, we performed preliminary experiments using agonists of TLRs. Preliminary data shows evidence of enteric neuronal damage by activation of TLRs. The overall goal of the present proposal is to characterize the role of oxidative stress in the pathogenesis of diabetic enteric neuropathy. Oxidative stress may lead to alteration in TLRs and activate of the NFKB pathway resulting in neuronal cell death. Antioxidants, [sic] may thus help decrease this neuropathy.
The specific aims (supported by preliminary data) follow the hypothesis stated below: [sic] ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK078552-01
Application #
7294718
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2007-09-01
Project End
2009-07-31
Budget Start
2007-09-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$76,500
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Chandrasekharan, B; Anitha, M; Blatt, R et al. (2011) Colonic motor dysfunction in human diabetes is associated with enteric neuronal loss and increased oxidative stress. Neurogastroenterol Motil 23:131-8, e26
Mwangi, Simon M; Usta, Yousef; Shahnavaz, Nikrad et al. (2011) Glial cell line-derived neurotrophic factor enhances human islet posttransplantation survival. Transplantation 92:745-51
Chandrasekharan, Bindu P; Kolachala, Vasantha L; Dalmasso, Guillaume et al. (2009) Adenosine 2B receptors (A(2B)AR) on enteric neurons regulate murine distal colonic motility. FASEB J 23:2727-34
Chandrasekharan, Bindu; Bala, Vanitha; Kolachala, Vasantha L et al. (2008) Targeted deletion of neuropeptide Y (NPY) modulates experimental colitis. PLoS One 3:e3304
Blatt, Richard; Srinivasan, Shanthi (2008) Defining disease with laser precision: laser capture microdissection in gastroenterology. Gastroenterology 135:364-9
Anitha, Mallappa; Joseph, Irene; Ding, Xiaokun et al. (2008) Characterization of fetal and postnatal enteric neuronal cell lines with improvement in intestinal neural function. Gastroenterology 134:1424-35