Homocysteine's role in Age-Related Macular Degeneration

同型半胱氨酸在年龄相关性黄斑变性中的作用

• 批准号: 10558578
• 负责人: Amany M Tawfik
• 金额: $ 36.24万
• 依托单位: OAKLAND UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10558578
• 关键词: Age related macular degeneration; Aging; Amino Acids; Biological Assay; Blindness; Blood; Cells; Choroidal Neovascularization; Cystathionine beta-Synthase; Data; Development; Dietary Supplementation; Elderly; Endothelial Cells; Endothelium; Enzymes; Evaluation; Exhibits; Experimental Models; Fluorescein Angiography; Folic Acid; Functional disorder; Genetic; Glycolysis; Glycolysis Induction; Goals; Homocysteine; Human; Hyperhomocysteinemia; In Vitro; Intestinal Absorption; Joints; Knockout Mice; Lasers; Life Expectancy; Mediating; Medical; Metabolic; Metabolism; Methylation; Mitochondria; Modality; Modeling; Modification; Molecular; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Optical Coherence Tomography; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Phenotype; Photoreceptors; Population; Prevalence; Proteins; Reporting; Respiration; Retina; Risk; Role; SLC2A1 gene; Serum; Signal Pathway; Signal Transduction; Structure of retinal pigment epithelium; Testing; Therapeutic; Tight Junctions; Up-Regulation; Vascular Endothelial Growth Factors; Vision Disorders; Vitamin B 12; Vitamin B6; Wild Type Mouse; bevacizumab; conditional knockout; electric impedance; experimental study; fluorescein isothiocyanate dextran; folic acid supplementation; gene therapy; genetic manipulation; in vivo; inhibitor; intravitreal injection; mouse model; overexpression; pharmacologic; preservation; prevent; receptor; retinal damage; therapeutic target

Summary/Abstract Age-related macular degeneration (AMD) is the leading cause of vision loss in among elderly populations. Elevated homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy) has been reported in patients with AMD; thereby suggesting an association between HHcy and the risk of AMD. Recently, we reported retinal changes similar to AMD in a mouse model of HHcy which lacks Cystathionine-β-synthase (cbs+/-) or received intravitreal injections of Hcy. These models showed significant retinal pigment epithelium (RPE) dysfunction and choroidal neovascularization (CNV) However, the lack of understanding the molecular/cellular mechanisms of these changes is a critical barrier in proposing Hcy as a therapeutic target in AMD. Our preliminary data show that HHcy-induced RPE dysfunction is associated with the upregulation of the N-methyl-D-aspartate (NMDAr) and GLUT1 receptors and increased glycolysis. Hence, we hypothesize that HHcy contributes to the pathogenesis of AMD via activation of the NMDAr and GLUT1 signaling pathways that induce the metabolic switch from oxidative phosphorylation to glycolysis. Therefore, elimination of excess Hcy through pharmacological or genetic intervention could be beneficial in the treatment of AMD. To test our hypothesis, we will conduct in vitro experiments, using RPE and choroidal endothelial cells (CEC) and in vivo using cbs+/-, wild type mice receiving intravitreal injection of Hcy and mice lacking the endothelial or RPE NMDAr (NMDAr-/-E or NMDAr-/-R respectively). Our specific aims include: 1: Testing the hypothesis that HHcy induces the metabolic switch from mitochondrial respiration to glycolysis via activation of GLUT1 in RPE cells: We will examine the changes in the retinal expression and localization of GLUT1, mitochondrial respiration, glycolysis and rate-limiting glycolytic enzymes in HHcy models. Moreover, we will determine the effect of GLUT1 inhibition on HHcy-induced RPE dysfunction and CNV. Aim 2: Testing the hypothesis that inhibition of NMDAr preserves RPE function and reduces the development of CNV under HHcy. We will examine the effects of pharmacological inhibition or genetic manipulation of the NMDAr on HHcy-induced RPE dysfunction and CNV. The effect of intravitreal injection of Hcy will be evaluated in NMDAr-/-E or NMDAr-/-R as compared to wild type and cbs+/- mice with or without NAMDAr inhibitors. Parallel in vitro experiments will be performed on RPE and CEC subjected to Hcy with or without NMDAr inhibitors followed by assessment of RPE function and angiogenic potential of CEC. Aim 3: Testing the hypothesis that elimination of excess Hcy by dietary supplementation or genetic/ pharmacological modifications prevents the progression of AMD. Hcy clearance will be enhanced in models of HHcy through two approaches, followed by assessment of RPE function and angiogenic potential of CEC: (a) Enhancing the remethylation pathway of Hcy metabolism using vitamins B6, B12 and folic acid supplementation. (b) Enhancing the transsulforation pathway of Hcy metabolism via CBS overexpression. Successful clearance of excess Hcy holds immense promise in the treatment of AMD.

摘要/文摘

项目成果

Patterns of Gene Expression, Splicing, and Allele-Specific Expression Vary among Macular Tissues and Clinical Stages of Age-Related Macular Degeneration.

基因表达、剪接和等位基因特异性表达的模式因黄斑组织和年龄相关性黄斑变性的临床阶段而异。

• DOI: 10.3390/cells12232668
• 发表时间: 2023-11-21
• 期刊: CELLS
• 影响因子: 6
• 作者: Shwani, Treefa;Zhang, Charles;Owen, Leah A.;Shakoor, Akbar;Vitale, Albert T.;Lillvis, John H.;Barr, Julie L.;Cromwell, Parker;Finley, Robert;Husami, Nadine;Au, Elizabeth;Zavala, Rylee A.;Graves, Elijah C.;Zhang, Sarah X.;Farkas, Michael H.;Ammar, David A.;Allison, Karen M.;Tawfik, Amany;Sherva, Richard M.;Li, Mingyao;Stambolian, Dwight;Kim, Ivana K.;Farrer, Lindsay A.;DeAngelis, Margaret M.
• 通讯作者: DeAngelis, Margaret M.

Isolation of Primary Mouse Retinal Pigmented Epithelium Cells.

• DOI: 10.3791/63543
• 发表时间: 2022-11-04
• 期刊: Journal of visualized experiments : JoVE
• 作者: Tomaszewski R;Rajpurohit P;Cheng M;Tawfik A
• 通讯作者: Tawfik A

Warburg Effect as a Novel Mechanism for Homocysteine-Induced Features of Age-Related Macular Degeneration.

• DOI: 10.3390/ijms24021071
• 发表时间: 2023-01-05
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Samra, Yara A.;Zaidi, Yusra;Rajpurohit, Pragya;Raghavan, Raju;Cai, Lun;Kaddour-Djebbar, Ismail;Tawfik, Amany
• 通讯作者: Tawfik, Amany

A novel interaction between soluble epoxide hydrolase and the AT1 receptor in retinal microvascular damage.

• DOI: 10.1016/j.prostaglandins.2020.106449
• 发表时间: 2020-06
• 期刊: Prostaglandins & other lipid mediators
• 影响因子: 2.9
• 作者: Wang MH;Ibrahim AS;Hsiao G;Tawfik A;Al-Shabrawey M
• 通讯作者: Al-Shabrawey M

Role of Endothelial ADAM17 in Early Vascular Changes Associated with Diabetic Retinopathy.

内皮 ADAM17 在与糖尿病视网膜病变相关的早期血管变化中的作用。

• DOI: 10.3390/jcm9020400
• 发表时间: 2020
• 期刊: Journal of clinical medicine
• 影响因子: 3.9
• 作者: Shalaby,Lamiaa;Thounaojam,Menaka;Tawfik,Amany;Li,Junnan;Hussein,Khaled;Jahng,WanJin;Al-Shabrawey,Mohamed;Kwok,HangFai;Bartoli,Manuela;Gutsaeva,Diana
• 通讯作者: Gutsaeva,Diana