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Glutaminase in Arterial Injury and Disease

谷氨酰胺酶在动脉损伤和疾病中的作用

基本信息

批准号：
10630196
负责人：
WILLIAM DURANTE
金额：
$ 39.07万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-23 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630196
关键词：
Acid-Base Equilibrium Ammonia Animals Apoptosis Arterial Injury Arteries Atherosclerosis Attenuated Biological Models Blood Vessels Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell Proliferation Cell physiology Collagen DNA biosynthesis Data Diabetes Mellitus Diabetic mouse Disease Enzymes Extracellular Signal Regulated Kinases Fibrosis Gene Delivery Gene Transfer Generations Genetic Glucose Glutamates Glutaminase Glutamine Goals Growth Factor Hypertension In Vitro Insulin-Dependent Diabetes Mellitus Laboratories Lesion Liver Fibrosis Mediating Mediator Metabolism Mitochondria Non-Insulin-Dependent Diabetes Mellitus Play Process Production Proliferating Proline Protein Isoforms Pulmonary Hypertension Regulation Risk Rodent Role Seminal Signal Transduction Smooth Muscle Myocytes Stroke Testing Time Transcription Factor AP-1 Transcriptional Activation United States Vascular Diseases Vascular Smooth Muscle Vascular remodeling adenoviral mediated angiogenesis arterial remodeling arterial stiffness cell motility cost diabetic diabetic patient experimental study heme oxygenase-1 in vivo Model injured migration mortality mouse model neointima formation neurotransmission new therapeutic target novel overexpression patient population percutaneous coronary intervention pharmacologic prevent response response to injury restenosis success tumor growth vascular abnormality vascular smooth muscle cell proliferation

项目摘要

PROJECT SUMMARY The broad long-term goal of this proposal is to establish the enzyme glutaminase-1 (GLS1) as a critical mediator of lesion formation in arterial injury and disease. GLS1 is a mitochondrial enzyme that metabolizes glutamine (Gln) to glutamate (Glu) and ammonia (NH3). GLS1 plays a critical role in neurotransmission, acid- base balance, angiogenesis, hepatic fibrosis, and tumor growth, but little is known regarding the function of GLS1 in vascular smooth muscle cells (SMCs). However, preliminary studies demonstrated that the proliferation, migration, and survival of SMCs is highly dependent on the presence of Gln. It was also discovered that SMCs exclusively express the GLS1 isoform, that overexpression of GLS1 stimulates SMC migration, and that inhibition of GLS1 activity or expression blocks SMC DNA synthesis or migration, respectively. Moreover, Glu, but not NH3, substitutes for Gln in promoting SMC proliferation and collagen synthesis. Additional experiments revealed that growth factors and glucose stimulate GLS1 activity in vascular SMCs. Final pilot experiments also demonstrated that arterial injury and diabetes induces the expression of GLS1 in the vessel wall, and that inhibition of GLS1 activity or genetic depletion of GLS1 attenuates neointima formation following arterial injury as well as arterial fibrosis and stiffening in diabetic animals. Based on these findings, it is proposed that GLS1 plays an integral role in aberrant arterial remodeling by stimulating SMC proliferation, migration, collagen synthesis, and survival by metabolizing Gln to Glu and NH3. This hypothesis will be tested in three interrelated specific aims. In aim 1, the role of GLS1 in regulating SMC function will be determined. These studies will investigate the effect of GLS1 gene delivery on SMC proliferation, migration, collagen synthesis and survival, and determine the role of the various GLS1 products on these processes. They will also explore if the induction of GLS1 by growth factors contributes to their ability to promote SMC proliferation, migration, and collagen synthesis. In aim 2, the role of GLS1 in regulating the arterial response to injury will be established. These studies will examine the time-course of GLS1 expression in injured rodent carotid arteries, and determine if pharmacological inhibition of GLS1 activity, silencing GLS1 expression, or genetic deletion of GLS1 in SMCs attenuates the remodeling response following arterial injury. In aim 3, the role of GLS1 in aberrant arterial remodeling and hypertension in diabetes will be investigated. These studies will examine the effect of glucose on GLS1 expression both in cultured vascular SMCs and in arteries from diabetic mice. In addition, they will examine if GLS1 contributes to glucose-mediated alterations in SMC function, arterial remodeling, and hypertension in diabetic mice. It is anticipated that these studies will establish GLS1 as a key regulator of SMC proliferation, migration, collagen synthesis, and survival. They may also also identify GLS1 and its products as novel contributors to lesion formation following arterial injury, and establish GLS1 as a new translational target in treating abnormal remodeling and hypertension in diabetes.

项目总结

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Arginine in COVID-19-Induced Immunopathology and Vasculopathy.

DOI：
10.3390/metabo12030240
发表时间：
2022-03-11
期刊：
Metabolites
影响因子：
4.1
作者：
Durante W
通讯作者：
Durante W

Canagliflozin Regulates Human Endothelial Cell Function: Role of Heme Oxygenase-1.

Canagliflozin 调节人内皮细胞功能：血红素加氧酶 1 的作用。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Durante,William;Behnammanesh,Ghazaleh;Durante,GiovannaL;Peyton,KellyJ
通讯作者：
Peyton,KellyJ

Glutamine Deficiency Promotes Immune and Endothelial Cell Dysfunction in COVID-19.