Browsing by Subject "diabetic retinopathy"
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Item A Look at Diabetes Mellitus and the Effects of a Study Drug on Diabetic Nephropathy(2002-08-01) Schlueter, Cynthia K.; Debbie Lewis; Clifton Cage; Rustin ReevesDuring my internship, I assisted with a twenty-four week, phase 2, double blinded, placebo controlled trial for a drug being developed to slow, if not prevent, the development of ESRD from overt neuropathy in patients with both type 1 and type 2 diabetes. This drug is a naturally occurring component of vitamin B6 and is an AGE-inhibitor. The AGE-inhibitory effect of the study drug was discovered by isolating Amadori products in the pathway to AGE formation. Once the intermediates were isolated, the sponsor’s scientists searched for compounds that could specifically block the conversion of these Amadori products into AGEs. The study drug was found to be a strong inhibitor of this pathway. In comparison, the common AGE inhibitor, aminoguanidine was found to be ineffective in blocking the post-Amadori foundation AGEs. Therefore, it must block AGE formation at one of the less clinically relevant pathways, and should be less effective in treating nephropathy according to the sponsor’s scientists. This study included type 1 and type 2 patients with clinically diagnosed diabetic retinopathy and a urinary albumin excretion rate (UAE) of greater than 300 mg/24h. Other inclusion and exclusion criteria were applied for the safety of the subjects and greater viability of the data.Item Characterization of the interactions of guanidine compounds with the human GABA-A ρ1 receptor(2015-12-01) Snell, Heather D.; Gonzales, Eric B.; Dillon, Glenn H.; Singh, MeharvanThis dissertation investigates the activity of guanidine compounds GMQ, and amiloride and its derivatives on the human GABA-A ρ1 receptor, compounds classified as antagonists for the heteromeric GABA-A αβγ receptor. The GABA-A ρ receptor possesses many differences in kinetics, expression, and pharmacology from the heteromeric GABA-A αβγ receptors. Many GABA-A αβγ receptors ligands interact differently, or fail to interact with, the GABA-A ρ receptor. Thus the activity of these guanidine compounds on the GABA-A ρ1 receptor remains unknown. Based on the differential pharmacology displayed by the GABA-A ρ receptors, we propose that GMQ and amiloride would interact with the GABA-A ρ1 receptor as agonists, different from their activity on the heteromeric GABA-A αβγ receptors. Importantly, our data demonstrates GMQ and amiloride interacts with the GABA-A ρ receptors as negative and positive allosteric modulators, respectively. The 15’ residue of the second transmembrane domain of the GABA-A ρ1 receptor is important in the positive allosteric modulatory mechanism, and the accessibility of the guanidine group on the guanidine compound is integral in the positive allosteric modulation mechanisms of amiloride and its derivative 5- (N,N-Hexamethylene) amiloride (HMA). The investigation of novel compounds that interact with the GABA-A ρ receptor differently from GABA-A αβγ receptor would contribute to a better understanding of the GABA-A ρ receptor structure and the production of novel therapeutics specific for the GABA-A ρ receptor. Particularly, the GABA-A ρ receptor is implicated in retinal hypoxic disorders such as diabetic retinopathy. These guanidine compounds could be utilized as a back-bone for the production of compounds that could alleviate the pathologies caused by advanced stages of diabetic retinopathy.Item Role of mitophagy in ocular neurodegeneration(Frontiers Media S.A., 2023-11-15) Brooks, Calvin D.; Kodati, Bindu; Stankowska, Dorota L.; Krishnamoorthy, Raghu R.Neurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both aerobically and anaerobically. Neurons have an abundance of mitochondria which generate adequate ATP to keep up with the high metabolic demand. One consequence of the oxidative phosphorylation mechanism of ATP synthesis, is the generation of reactive oxygen species which produces cellular injury as well as damage to mitochondria. Mitochondria respond to injury by fusion which serves to ameliorate the damage through genetic complementation. Mitochondria also undergo fission to meet an increased energy demand. Loss of mitochondria is also compensated by increased biogenesis to generate new mitochondria. Damaged mitochondria are removed by mitophagy, an autophagic process, in which damaged mitochondria are surrounded by a membrane to form an autophagosome which ultimately fuses with the lysosome resulting in degradation of faulty mitochondria. Dysregulation of mitophagy has been reported in several central nervous system disorders, including, Alzheimer's disease and Parkinson's disease. Recent studies point to aberrant mitophagy in ocular neurodegenerative disorders which could be an important contributor to the disease etiology/pathology. This review article highlights some of the recent findings that point to dysregulation of mitophagy and it's underlying mechanisms in ocular neurodegenerative diseases, including, glaucoma, age-related macular degeneration and diabetic retinopathy.