STRA6 and Ocular Vitamin A Homeostasis

STRA6 和眼部维生素 A 稳态

基本信息

批准号：
10735070
负责人：
Johannes Friedrich von Lintig
金额：
$ 47.34万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735070
关键词：
11 cis Retinal Adolescence Adult Affect All-Trans-Retinol Architecture Beta Carotene Binding Biochemical Blood-Retinal Barrier Bruch&apos s basal membrane structure Chronic Chronic Disease Chylomicrons Clinical Research Complex Cone Dietary Intervention Disease Dose Enterocytes Esters Etiology Eye Eye Development Eye diseases Fat-Soluble Vitamin Foundations Funding Genetic Goals Health Hepatic Hereditary Disease Homeostasis Hormones Human Imaging Techniques Impairment Inherited Intestines Knockout Mice Knowledge Life Light Liver Maintenance Mammals Mediating Membrane Membrane Proteins Metabolism Methodology Molecular Mus Night Blindness Organizational Change Outcome Oxygenases Pathologic Pathway interactions Patients Peripheral Photoreceptors Physiological Pigments Play Positioning Attribute Process Production Provitamin A Carotenoid RBP4 gene Reagent Regulation Research Research Design Retina Retinal Cone Retinal Pigments Retinitis Pigmentosa Retinoids Retinol Binding Proteins Role Signal Transduction Structure Structure of retinal pigment epithelium Supplementation Syndrome System Therapeutic Intervention Tight Junctions Tissues Transgenic Mice Tretinoin Vertebrate Photoreceptors Vision Visual impairment Vitamin A Vitamin A Deficiency absorption alpha-carotene basolateral membrane chromophore clinically relevant dietary genetic approach high resolution imaging improved induced pluripotent stem cell innovation lipoprotein lipase loss of function monolayer mouse model novel organizational structure receptor retinal neuron retinal rods therapeutic development tool transcription factor uptake

项目摘要

ABSTRACT The fat-soluble vitamin A (all-trans-retinol) is distributed in the body to maintain retinoid signaling in peripheral tissues and vision in the eyes. This transport occurs via an extrinsic pathway for the distribution of dietary vitamin A in the form of retinyl esters in chylomicrons and an intrinsic pathway for the distribution of vitamin A from hepatic stores bound to the retinoid binding protein RBP4. Cellular uptake of vitamin A from these two transport modes is facilitated by lipoprotein lipase and by the RBP4 receptor STRA6 (Stimulated by Retinoic Acid 6), respectively. Disrupted vitamin A transport is a serious health problem and is associated with blinding diseases ranging from night blindness to complex ophthalmic syndromes. We propose to study the etiology of ocular diseases states that are associated with perturbed ocular vitamin A uptake homeostasis by comparing the eyes of STRA6-deficient and that of control mice. In Aim 1, we will examine the role of STRA6 in the functioning of the outer blood-retinal barrier. We will study whether ocular vitamin A deficiency in Stra6 knockout mice impairs the structural integrity and functioning of this barrier. Additionally, we will examine whether retinoid signaling regulates the expression of key components of both the outer blood-retina barrier in mice and human retina pigment epithelium cells derived from inducible pluripotent stem cells. In Aim 2, we will use Stra6 knockout mice to analyze the consequences of imbalances in ocular retinoid concentrations on rod and cone photoreceptor function and ultrastructure. We will generate novel transgenic mouse lines to examine the competition between rods and cones for limited chromophore in the STRA6-deficient eyes. This research will address the question whether the STRA6/RBP4-dependent transport system is an adaption to the high chromophore demand from rod photoreceptors. In Aim 3, we will study whether manipulation of the extrinsic pathway can rescue cone and rod photoreceptor function in STRA6-deficiency and whether the STRA6/RBP4 uptake system provides selectivity for the uptake of canonical retinoids. Collectively, our proposed studies will advance knowledge about ocular vitamin A homeostasis by elucidating its mechanisms in the physiological state and by studying the consequences of its loss-of-function in disease states.

抽象的脂溶性维生素A（全反元素）分布在体内以维持类维生素的信号传导在眼睛中的周围组织和视力中。这种运输是通过外在途径进行的在乳糜微粒中以视网膜酯的形式分布饮食维生素A的分布和固有的从结合类维生素的结合蛋白的肝存储中维生素A分布的途径 RBP4。脂蛋白促进了这两种传输模式的维生素A的细胞摄取脂肪酶和RBP4受体Stra6（由视黄酸6刺激）。破坏了维生素A运输是一个严重的健康问题，与盲目疾病有关从夜失明到复杂的眼科综合征。我们建议研究与扰动眼维生素摄取稳态相关的眼部疾病状态通过比较Stra6缺陷型和对照小鼠的眼睛。在AIM 1中，我们将检查Stra6在外部血视网膜屏障功能中的作用。我们将研究Stra6敲除小鼠中的眼部维生素A缺乏症会损害结构该障碍的完整性和功能。此外，我们将检查性类视黄度信号调节小鼠外血性屏障的关键成分的表达和人视网膜色素上皮细胞衍生自诱导多能干细胞。在AIM 2中，我们将使用Stra6敲除小鼠分析眼类维生素的失衡后果杆和锥形感光器功能和超微结构的浓度。我们将生成小说转基因小鼠线以检查有限的杆和锥之间的竞争在Stra6缺陷眼中发色团。这项研究将解决以下问题 Stra6/rbp4依赖性运输系统是对高发色团需求的适应杆感光体。在AIM 3中，我们将研究对外部途径的操纵是否可以 Stra6缺乏率以及是否stra6/rbp4，救援锥和杆光感受器功能吸收系统为摄取的摄取性类维生素提供了选择性。总体而言，我们提出的研究将通过阐明它生理状态的机制并通过研究其功能丧失的后果在疾病状态。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development and validation of a method to deliver vitamin A to macrophages.

DOI：
10.1016/bs.mie.2022.04.008
发表时间：
2022
期刊：
Methods in enzymology
影响因子：
0
作者：
通讯作者：

Carotenoid modifying enzymes in metazoans.

DOI：
10.1016/bs.mie.2022.05.005
发表时间：
2022
期刊：
Methods in enzymology
影响因子：
0
作者：
通讯作者：

Astaxanthin-Shifted Gut Microbiota Is Associated with Inflammation and Metabolic Homeostasis in Mice.

DOI：
10.1093/jn/nxaa222
发表时间：
2020-08
期刊：
The Journal of nutrition
影响因子：
0
作者：
Lei Wu;Yi Lyu;Ramkumar Srinivasagan;Jin-Long Wu;Babajide A. Ojo;Minghua Tang;Guadalupe Davila El-Rassi;Katherine Metzinger;Brenda J. Smith;E. Lucas;S. Clarke;Winyoo Chowanadisai;Xinchun Shen;Hui He;T. Conway;Johannes von Lintig-Johannes-von Lintig-2126121506;Dingbo Lin
通讯作者：
Lei Wu;Yi Lyu;Ramkumar Srinivasagan;Jin-Long Wu;Babajide A. Ojo;Minghua Tang;Guadalupe Davila El-Rassi;Katherine Metzinger;Brenda J. Smith;E. Lucas;S. Clarke;Winyoo Chowanadisai;Xinchun Shen;Hui He;T. Conway;Johannes von Lintig-Johannes-von Lintig-2126121506;Dingbo Lin

Disturbed retinoid metabolism upon loss of rlbp1a impairs cone function and leads to subretinal lipid deposits and photoreceptor degeneration in the zebrafish retina.