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Nitric oxide (NO) is an important signaling molecule in the cardiovascular and neuronal systems. Reduced bioavailability and signaling resulting from debilitated production of NO by the endothelial nitric oxide synthase are central to the pathogenesis of cardiovascular disorders.
Two biochemical pathways accomplish NO signaling. The first is the Nobel Prize winning canonical pathway in which NO binds to the heme of the soluble guanylate cyclase (sGC) leading to activation and production of the secondary messenger cyclic guanosine monophosphate (cGMP). cGMP activates protein kinases leading to the phosphorylation of client proteins and amplification of NO signaling. The selective posttranslational modification of cysteine residues to form S-nitrosocysteine in proteins offers a secondary signaling pathway. Despite this knowledge, how these two pathways are coordinated, prioritized, and integrated at the proteome level remains unclear.
The research in the Ischiropoulos Lab aims to fill this unmet need by using mass spectrometry-based proteomic technologies to resolve simultaneously at the proteome level the NO signaling pathways during development and during aging.
Mitochondrial fatty acid β-oxidation is the primary pathway for the metabolism and conversion of long-chain fatty acids (LCFA) to energy. Defects in nuclear genes encoding for enzymes and transporters of the LCFA oxidation pathway cause a family of rare inherited autosomal recessive diseases that present with cardiomyopathy, intermittent muscle breakdown and liver failure. Routine screening of newborns for these disorders adverts life-threatening complications. Clinical management includes the avoidance of dietary intake of long-chain fatty acids, a high carbohydrate diet supplemented with medium chain triglyceride and in some cases, carnitine. Notwithstanding the advances in detection and clinical management, patients with these disorders still experience life-long complications such as recurrent myopathy, rhabdomyolysis, and cardiomyopathy.
Since current treatments and clinical management target only the symptoms, there is an unmet need to develop evidence-based corrective therapies for these inborn errors of metabolism.
- Synthesis of innovative multifunctional hybrid molecules as potential therapeutics for LCFA oxidation disorders. These molecules are tested in fibroblasts from patients with mutations in carnitine palmitoyltransferase-2, very long chain acyl CoA dehydrogenase, and mitochondrial trifunctional protein.
- Using mass spectrometry-based proteomic technologies we aim to identify and quantify the full spectrum of nitric oxide-induced post-translational modifications in the cardiovascular system providing for the first time a system-level appreciation of nitric oxide signalling.
Research Professor of Pediatrics and Systems Pharmacology and Translational Therapeutics
Dr. Ischiropoulos's research objectives are to develop and test novel therapeutics for long-chain fatty acid oxidation (LCFA) disorders, a collection of inherited metabolic diseases that affect the heart, liver and muscle. A second area of interest is the resolution of the nitric oxide signaling pathways at the proteome level in the cardiovascular and neuronal systems.