Document text
Principal Investigator: PANDU R GANGULA
Organization: MEHARRY MEDICAL COLLEGE
Fiscal Year: 2024
Award: $145,500
Funding agency: National Institute of General Medical Sciences
Diabetes Mellitus (DM) and periodontal diseases (PD) are complex chronic diseases with an established
bidirectional relationship. People with PD have two to three times the risk of having a heart attack, stroke, or
serious cardiovascular complications. PD in individuals with diabetes contributes to aggravated inflammatory
response leading to vascular disease (VD). Our group has previously shown that PD increases coronary heart
disease in diabetic patients. Nitric oxide (NO) mediated endothelial dysfunction is the initial step in the
development of VD. Reduced NO bioavailability due to the lack of tetrahydrobiopterin [BH4, a cofactor for
endothelial nitric oxide synthase (eNOS)], resulting in eNOS uncoupling, increases oxidative
stress/inflammation, impaired vascular smooth muscle relaxation and contributes to CV pathologies in diabetic
patients and rodent models of diabetes. Our previous studies demonstrated that chronic periodontal infection
reduced circulatory BH4 and NO levels and this reduction correlated with impaired immune signaling. In addition,
decreased levels of nuclear factor (erythroid-derived-2)-like 2 (Nrf2)-dependent antioxidants and increased
levels of reactive oxygen species (ROS) also play a critical role in hypertension and vascular function. We
recently reported that primary human aortic endothelial cells (pHAECs) infected with Porphyromonas gingivalis
(Pg, a major periodontal pathogen), exhibited reduced cell viability, elevated pro-inflammatory cytokines,
reduced Nrf2/eNOS and BH4 biosynthesis. In addition, our in-vivo rodent studies demonstrate that chronic
polybacterial periodontal infection [Pg, Treponema denticola (Td), and Fusobacterium nucleatum (Fn), a model
of PD in humans] reduced the protein expression of Nrf2/BH4/nNOS in resistance blood vessels of the infected
mice. However, the specific mechanisms that contribute to aggravated inflammation and oxidative stress during
PD and diabetes leading to endothelial dysfunction is completely unknown. Our central hypothesis is that BH4
regulates NO-mediated vascular function, which is greatly impaired in diabetic PD compared to diabetes or PD
alone. The specific aims are,1: To determine whether hyperglycemia (HG) aggravates PD-induced impairment
in BH4/NOS and NO downstream signaling in pHAECs. 2: To investigate whether increased endogenous BH4
biosynthesis suppresses PD/T2DM induced inflammation, oxidative stress and restores eNOS activity, NO
synthesis, and NO mediated vascular relaxation. The proposed studies will be the first to determine the role of
periodontal pathogens in NO-mediated vascular function in T2DM animal models. The research outlined in these
aims has translational relevance, as it has the potential to identify novel treatment; options for PD/T2DM induced
VD.
Terms: <2-amino-6-(S)-lactoyl-7,8-dihydro-4(3H)- pteridinone><ATP-protein phosphotransferase><Active Oxygen><Adult-Onset Diabetes Mellitus><Anabolism><Animal Model><Animal Models and Related Studies><Antioxidants><Aorta><Apoplexy><Attenuated><BH4><BPH4><Bacteroides gingivalis><Bioavailability><Biological Availability><Blood Vessels><Brain Vascular Accident><Buccal Cavity><Buccal Cavity Head and Neck><C fusiforme><C. fusiforme><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cavitas Oris><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Chronic><Chronic Disease><Chronic Illness><Chronic Periodontitis><Collaborations><Communicable Diseases><Complex><Coronary Disease><Coronary heart disease><Corynebacterium fusiforme><Cyclic GMP><Data><Development><Diabetes Mellitus><Dietary Supplementation><Dimerization><ENOS><Early Diagnosis><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelial Nitric Oxide Synthase><Endothelium-Derived Nitric Oxide><Enzyme Gene><Enzymes><Erythroid><Event><Exhibits><F fusiformis><F nucleatum><F nucleatus><F. fusiformis><F. nucleatum><F. nucleatus><Female><Forsythia><Fusiformis fusiformis><Fusiformis nucleatus><Fusobacterium nucleatum><GUCY><Goals><Goldenbells><Gram-Negative Bacteria><Guanosine Cyclic Monophosphate><H4B><H4biopterin><Heart Vascular><Human><Hyperglycemia><Hypertension><Immune signaling><Impairment><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Intracellular Communication and Signaling><Investigators><Ketosis-Resistant Diabetes Mellitus><Kinase Family Gene><Laboratories><Lian qiao><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Mononitrogen Monoxide><Mouth><Murine><Mus><Muscle Relaxation><Muscle relaxation phase><Myocardial Infarct><Myocardial Infarction><NIDDM><NOS3><NOS3 gene><Nitric Oxide><Nitric Oxide Synthase 3><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nuclear><Oral cavity><Oxidative Stress><Oxygen Radicals><P gingivalis><P. gingivalis><Parodontosis><Pathogenesis><Pathology><Pathway interactions><Periodontal Diseases><Periodontal Infection><Periodontitis><Persons><Physiologic Availability><Play><Porphyromonas gingivalis><Pro-Oxidants><Protein Dimerization><Protein Kinase><Publications><Reactive Oxygen Species><Relaxation><Reporting><Research><Research Personnel><Researchers><Resistance><Risk><Rodent><Rodent Model><Rodentia><Rodents Mammals><Role><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Soluble Guanylate Cyclase><Soluble Guanylyl Cyclase><Stable Diabetes Mellitus><Stroke><Supplementation><T denticola><T. denticola><T2 DM><T2D><T2DM><THBP><Testing><Texas><Time><Treponema denticola><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Type III nitric oxide synthase><Vascular Diseases><Vascular Disorder><Vascular Endothelium><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Smooth Muscle><adult onset diabetes><anti-oxidant enzyme><antioxidant enzyme><atherosclerotic heart disease><attenuate><attenuates><biological signal transduction><biosynthesis><blood vessel disorder><brain attack><cGMP><cardiac infarct><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><cerebral vascular accident><cerebrovascular accident><chronic disorder><circulatory system><cofactor><college><collegiate><coronary attack><coronary disorder><coronary infarct><coronary infarction><cytokine><developmental><diabetes><diabetic><diabetic patient><diet supplementation><disease model><disorder model><early detection><effective intervention><endothelial cell derived relaxing factor><endothelial dysfunction><enzyme activity><enzyme biosynthesis><experience><glycogen synthase a kinase><heart attack><heart infarct><heart infarction><high blood pressure><hydroxyalkyl protein kinase><hyperglycemic><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><improved><in vivo><infection mouth><ketosis resistant diabetes><male><maturity onset diabetes><model of animal><nitric oxide receptor><nitric oxide-sensitive guanylyl cyclase><non-diabetic><nondiabetic><novel><oral infection><oral infectious><oral microbial community><oral microbiota><oral microflora><oxidation><pathogen><pathway><periodontal disorder><periodontal pathogen><periodontium disease><periodontium disorder><periodontopathogen><periopathogen><periopathogenic><phosphorylase b kinase kinase><protein expression><resistant><sGC protein><sepiapterin><social role><stroked><strokes><tetrahydrobiopterin><type 2 DM><type II DM><type two diabetes><vascular><vascular dysfunction><vascular endothelial dysfunction><vasculopathy>