Our application belongs to the theme, """"""""Translating Basic Science Discoveries into New and Better Treatments"""""""". The goal of the project is to develop the first selective adenosine monophosphate deaminase- 2 (AMPD2) inhibitor, which we believe will offer an important new method of treatment for diseases of metabolic syndrome. AMPD2 is the predominant AMP isoform that is present in liver and drives the reaction of AMP to IMP (inosine monophosphate) and downstream products such as uric acid. Our preliminary data suggests that AMPD2 is the key enzyme that switches mammals from fat utilizing to fat accumulating, and that activation of this pathway results in the inhibition of AMP kinase, a key enzyme that directs fat utilization and a reduction in fat synthesis. We have indirect evidence that the AMPD pathway is down-regulated by hibernating animals as they enter torpor, thus allowing them to activate AMP kinase and initiate fat degradation as a means to utilize stored energy. In contrast, humans appear to be """"""""locked in"""""""" to be fat accumulating due to two mechanisms: first, evolution has provided a human mutation in uricase that results in high uric acid, which we have found further up-regulates AMPD2, and second, because of the marked intake of fructose present in added sugars of the human diet that also stimulates AMPD2 along with providing substrate. Inhibition of AMPD2 appears to be a novel mechanism for preventing and treating metabolic syndrome, obesity, diabetes and cardiovascular disease. In this proposal we will both complete a proof of concept (Specific Aim 1) and develop the first of a new class of drugs that will target the key isoform of AMPD that is driving this process (AMPD2) (Specific Aim 2).
Aim 1 will evaluate the role for AMPD2 in inducing metabolic syndrome. This will consist of cell culture studies (using siRNA or drugs generated that block AMPD2 activity) and animal studies (by creating transgenic and knockout AMPD2 mice) under both normal conditions and following the administration of a high fructose or high fat diet. We will also evaluate the role of AMPD2 inhibitors generated from Aim 2 as it relates to efficacy, specificity and toxicity in cell culture and animal models.
Aim 2 will focus on drug discovery and development and will use three approaches;a) molecular modeling aided design and optimization of a selective AMPD2 inhibitor based on modification of the imidazodiazepine ring of coformycin, a known but nonselective inhibitor;b) molecular modeling based on the first crystal structure of human AMPD2 ( to be obtained with the University of Colorado X-ray Core Facility) in the presence or absence of inhibitors;and, c) by high- throughput screening for novel prototype selective inhibitors of AMPD2. By combining the expertise of the basic science laboratory of Dr. Johnson with the highly experienced drug design team from Amidaerus, we expect to develop the first AMPD2 inhibitor that will be ready for Phase I trials at the end of the 3 year period.
Identifying novel pathways for the etiology of obesity and metabolic syndrome, and potentially new therapies, is the topic of this application. Specifically, we have identified a role for adenosine monophosphate deaminase-2 (AMPD2) in driving key processes that lead to fat accumulation and insulin resistance, and in this application we propose studies to develop the first AMPD2 inhibitor which we predict will provide a major new approach for preventing and treating obesity, hypertension, metabolic syndrome, and diabetes.
|Lanaspa, Miguel A; Epperson, L Elaine; Li, Nanxing et al. (2015) Opposing activity changes in AMP deaminase and AMP-activated protein kinase in the hibernating ground squirrel. PLoS One 10:e0123509|
|Cicerchi, Christina; Li, Nanxing; Kratzer, James et al. (2014) Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J 28:3339-50|
|Lanaspa, Miguel A; Ishimoto, Takuji; Cicerchi, Christina et al. (2014) Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 25:2526-38|
|Lanaspa, Miguel A; Ishimoto, Takuji; Li, Nanxing et al. (2013) Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun 4:2434|
|Feig, Daniel I; Madero, Magdalena; Jalal, Diana I et al. (2013) Uric acid and the origins of hypertension. J Pediatr 162:896-902|
|Johnson, Richard J; Stenvinkel, Peter; Martin, Sandra L et al. (2013) Redefining metabolic syndrome as a fat storage condition based on studies of comparative physiology. Obesity (Silver Spring) 21:659-64|
|Madero, Magdalena; Lozada, Laura Gabriela Sánchez; Johnson, Richard J (2012) Fructose likely does have a role in hypertension. Hypertension 59:e54; author reply e55-6|
|Lanaspa, Miguel A; Sanchez-Lozada, Laura G; Cicerchi, Christina et al. (2012) Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One 7:e47948|
|Sánchez-Lozada, Laura Gabriela; Lanaspa, Miguel A; Cristóbal-García, Magdalena et al. (2012) Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp Nephrol 121:e71-8|
|Lanaspa, Miguel A; Cicerchi, Christina; Garcia, Gabriela et al. (2012) Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver. PLoS One 7:e48801|
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