EXCEED THE SPACE PROVIDED. _ Compelling experimental and epidemiological evidence indicates that environmental factors can play acrucial role inthecritical depletion of an essential mass of pancreatic IJ-cells in insulin-dependent diabetes mellitus. Additionally, functional alterations in B-cells, similar to those seen in noninsulin-dependent diabetes mellitus, have been produced in laboratory animals following exposure to the naturally-occurring compounds. For this competitive renewal, the objective will continue to be theelucidation of the mechanisms by which xenobiotics interact with B-cells to either kill these cells directly or to cause their functional impairment. One or more of these molecular mechanisms may initiate pathologic events that culminate in specific formsof diabetes mellitus. Because of the progress made in the preceding funding period, work in this application is structured to focus primarily upon mitochondrial DNA.
Four specific aims are proposed to pursue the objective. The first is to determine the effects of mtDNA damage on transcriptionof mtDNA, ATP productionand glucose-induced insulin secretion in P-cells. These studies are structured to determine how a change in the lesion equilibrium in mtDNA can precipitate alterations in its transcription which can lead to impaired glucose-induced insulin secretion.
The second aim i s to assess how mtDNA repair mechanisms in (3-cells affect the reestablishment of the normal lesion equilibrium in mtDNA. These studies will employ cultured P-cells to answer questions relatingto the hypothesis that the ability of P-cells to repair lesions in theirmtDNA is a key component in the maintenance of a normal lesion equilibrium. Defects in this repair allowthe lesion equilibrium in mtDNA to rise out of control and initiate some of the phenotypes associated with IDDM and NIDDM.
The third aim i s structured to determine how mtDNA repair is involved with apoptosis. The studies in this aim are designed to explore how changes in the lesion equilibrium in mtDNA in p-cells following oxidative stress can initiate mechanisms which induce apoptosis.
The final aim will evaluate the effects of recombinant DNA repair proteins targeted to the mitochondria.These experiments will use specific DNA repair sroteins that have been genetically-engineered to target them to the mitochondria in P-cells in order to restore a normallesion equilibrium following oxidative stress and other types of mtDNA damage. These studies will help provide a definitive answer concerning the role of mitochondrial DNA repair mechanisms in the p-cell dysfunction and death seen in diabetes mellitus. When successfully completed, these studies will provide a more complete understandingof the mechanisms by which xenobiotics can selectively interact with normal B-cellsto cause functional impairment and/or the death of these cells. PERFORMANCE SITE ========================================Section End===========================================
|Danobeitia, Juan S; Chlebeck, Peter J; Shokolenko, Inna et al. (2017) Novel Fusion Protein Targeting Mitochondrial DNA Improves Pancreatic Islet Functional Potency and Islet Transplantation Outcomes. Cell Transplant 26:1742-1754|
|Shokolenko, Inna N; Wilson, Glenn L; Alexeyev, Mikhail F (2016) The ""fast"" and the ""slow"" modes of mitochondrial DNA degradation. Mitochondrial DNA A DNA Mapp Seq Anal 27:490-8|
|Guarini, Giacinta; Kiyooka, Takahiko; Ohanyan, Vahagn et al. (2016) Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage. Basic Res Cardiol 111:29|
|Yang, Xi-Ming; Cui, Lin; White, James et al. (2015) Mitochondrially targeted Endonuclease III has a powerful anti-infarct effect in an in vivo rat model of myocardial ischemia/reperfusion. Basic Res Cardiol 110:3|
|Shokolenko, Inna N; Fayzulin, Rafik Z; Katyal, Sachin et al. (2013) Mitochondrial DNA ligase is dispensable for the viability of cultured cells but essential for mtDNA maintenance. J Biol Chem 288:26594-605|
|Alexeyev, Mikhail; Shokolenko, Inna; Wilson, Glenn et al. (2013) The maintenance of mitochondrial DNA integrity--critical analysis and update. Cold Spring Harb Perspect Biol 5:a012641|
|Shokolenko, Inna N; Wilson, Glenn L; Alexeyev, Mikhail F (2013) Persistent damage induces mitochondrial DNA degradation. DNA Repair (Amst) 12:488-99|
|Yuzefovych, Larysa; Wilson, Glenn; Rachek, Lyudmila (2010) Different effects of oleate vs. palmitate on mitochondrial function, apoptosis, and insulin signaling in L6 skeletal muscle cells: role of oxidative stress. Am J Physiol Endocrinol Metab 299:E1096-105|
|Grishko, V I; Ho, R; Wilson, G L et al. (2009) Diminished mitochondrial DNA integrity and repair capacity in OA chondrocytes. Osteoarthritis Cartilage 17:107-13|
|Rachek, Lyudmila I; Yuzefovych, Larysa V; Ledoux, Susan P et al. (2009) Troglitazone, but not rosiglitazone, damages mitochondrial DNA and induces mitochondrial dysfunction and cell death in human hepatocytes. Toxicol Appl Pharmacol 240:348-54|
Showing the most recent 10 out of 76 publications