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Inborn Errors of Long Chain Fat Metabolism

长链脂肪代谢先天性错误

基本信息

批准号：
8367859
负责人：
GERARD VOCKLEY
金额：
$ 32.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8367859
关键词：
Acyl CoA Dehydrogenases Affect Biochemical Biogenesis Biological Assay Carbon Cells Chemicals Clinical Collaborations Complex Cryoelectron Microscopy Data Disease Electron Transport Enzymes Equilibrium Exhibits Fatty Acids Frequencies Funding Generations Genes Genetic Genotype Goals Grant Hereditary Disease Human Inborn Genetic Diseases Incidence Knock-out Knockout Mice Lead Learning Left Lipids Liver Failure Location Long-Chain-Acyl-CoA Dehydrogenase Lung diseases Metabolic Metabolism Mitochondria Mus Mutation Null Lymphocytes Pathway interactions Patients Phenotype Physiological Play Point Mutation Process Production Proteins Pulmonary Surfactants Rattus Recurrence Reporting Respiratory Chain Role Sampling Side Structure Structure-Activity Relationship Symptoms Transfection acyl-CoA dehydrogenase clinical effect crosslink enzyme activity enzyme deficiency expression vector fatty acid oxidation fatty acid oxidation complex genetic pedigree lipid metabolism long chain fatty acid mouse model mutant novel null mutation oxidation pneumocyte protein complex protein structure protein structure function reconstitution repository research study surfactant surfactant deficiency tissue culture

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial fatty acid ¿-oxidation is traditionally viewed as an energy-generating, catabolic pathway but intermediates of this pathway can serve as key substrates for synthesis of other complex lipids. The long range objective of this project is to define the role of fatty acid oxidaton proteins in intermediary metabolism and the clinical impact of their deficiency due to inborn errors. The goal of the first funding period was to characterize the functional roles of LCAD, VLCAD, and ACAD9 and to explore the ramifications of genetic deficiencies of these enzymes in humans and mouse models. Significant progress has been made on each of these aims. Our chief findings include the ground breaking identification and partial purification of a multifunctional fatty acid oxidation complex containing all of the activities of this pathway in association with the mitochondrial respiratory chain super complexes and identification of the first patient with LCAD deficiency, presenting as predicted with a surfactant deficiency. The goal of this renewal application is to examine the expanding role of long chain fatty acid oxidation in normal metabolism and disease. It has three specific aims. Specific Aim 1 is to characterize the structure of the multifunctional fatty acid oxidation complex and its interaction with the mitochondrial respiratory chain. I hypothesize that this contact is critical to the channeling of reducing equivalents from fatty acid oxidation to the respiratory chain and that disruption of this process reduces the efficiency of mitochondrial energy generation. Specific Aim 1a is to elucidate the mechanism of electron transfer by first deducing the structure of the multifunctional FAOD complex using cryoelectron microscopy. Specific Aim 1b is to examine the role of patient identified mutations on VLCAD function, including their effect on the integrity of the FAOD multifunctional complex. Specific Aim 1c is to characterize the integrity of the fatty acid oxidatin complex in VLCAD and LCAD deficient mouse models. Specific Aim 2 is to characterize the disparate effects of null and point mutations in the ACAD9 gene on protein structure and function. I hypothesize that ACAD9 serves a duel function in mitochondria as a metabolic enzyme and a respiratory chain assembly/stability factor. Specific Aim 2a is to examine the metabolic and moonlighting functions of ACAD9 in cells from deficient human patients. Specific Aim 2b is to characterize the range of biochemical and clinical effects in an ACAD9 knock out mouse model. Specific Aim 3 is to further characterize LCAD deficiency in patients and a knock out mouse model, and to elucidate its function in surfactant metabolism. Specific Aim 3a is to examine surfactant metabolism in wild type and LCAD deficient primary pneumocytes. Specific Aim 3b is to characterize the incidence and spectrum of clinical symptoms in LCAD deficiency. PUBLIC HEALTH RELEVANCE: The acyl-CoA dehydrogenases are important enzymes in maintaining normal chemical balance in the body. We have identified two new genetic disorder of one of these enzymes that leads to liver failure and lung disease. Studying these disorders is important to learn more about their clinical presentation and treatment.

描述（由申请人提供）：