Chemical Biology of the Visual Pigments
视觉颜料的化学生物学
基本信息
- 批准号:10566896
- 负责人:
- 金额:$ 48.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:ARRB1 geneAccelerationAddressAffectAgonistAntibodiesArchitectureBindingBiochemicalBiological AssayBiologyChemicalsChemistryComplexConeCrystallographyDark AdaptationDependenceDetergentsDeuteriumDevelopmentDiseaseGasesGleanHeartHumanHydrolysisIn VitroIsomerismIsotopesKineticsKnockout MiceKnowledgeLibrariesLightLight AdaptationsLipidsMass Spectrum AnalysisMembraneMembrane ProteinsMethodologyMethodsMicellesModelingMolecularMolecular ConformationMusMutagenesisNatural regenerationNatureOcular PhysiologyOpsinPenetrationPharmacodynamicsPhasePhospholipidsPhotobleachingPhotochemistryPhotonsPhototransductionPhysiologicalPhysiologyPigmentsPlayProcessPropertyProtein ConformationProteinsReactionResearchRetinaRetinal ConeRetinal DiseasesRetinal PigmentsRetinaldehydeRhodopsinRod Outer SegmentsRoleSamplingSchiff BasesSeriesSignal TransductionStimulusStructureStructure-Activity RelationshipSurfaceTechniquesTestingTimeVertebrate PhotoreceptorsVisionVisualabsorptionchromophorecis trans isomerizationexperienceexperimental studyextracellularin vivoinsightinterestmetarhodopsinmouse modelmutantnanobodiesnovelnovel strategiespharmacokinetics and pharmacodynamicspharmacologicphotoactivationreceptorregenerativeresponsesensorsmall moleculesmall molecule therapeuticsstructural biologytherapeutic candidatetoolvisual cycle
项目摘要
ABSTRACT: Visual pigments initiate the human visual experience, making them of great physiological interest,
and also are affected in retinal diseases. Accordingly, numerous research efforts have been devoted to
characterizing their structure-function relationships. Despite these efforts, critical gaps remain in our
understanding of visual pigment photochemistry and signaling properties. Knowledge of this fundamental visual
physiology is necessary to make accelerated progress in developing treatments for associated retinopathies. At
the heart of all visual pigments is a retinaldehyde chromophore that undergoes a cis-trans isomerization upon
absorption of a photon of a suitable wavelength. This complex reaction, which proceeds through several
photointermediates, triggers the conformational changes necessary for the propagation of a light stimulus into a
biochemical response. This photoactivation process ends with the hydrolysis and release of retinaldehyde, which
is required for renewal of the receptor light-sensitive state and hence continuous visual function. Fundamental
questions remain regarding receptor structure, mechanisms and modulators of hydrolysis of the retinaldehyde
Schiff base, and the modes of interaction of small molecule therapeutic candidates.
Here, we will pursue four specific aims that employ newly developed tools and approaches that we believe will
overcome previously insurmountable experimental challenges. 1) Elucidate structures of rhodopsin
photointermediates stabilized by nanobodies. Using a novel series of camelid antibodies that arrest the
rhodopsin photocycle, we will perform a detailed structure-function characterization of metarhodopsin
intermediates. 2) Define the kinetics of hydrolysis of the retinaldehyde chromophores of rhodopsin and cone
opsin pigments in native membranes. We have developed a novel mass spectrometry-based method that can,
for the first time, directly detect the retinal conjugation state of visual pigments in native membranes; we will
use this method to determine key rate constants necessary to model the interplay between visual pigment
bleaching cycles and the regenerative visual cycles. 3) Assess the influence of cytosolic effectors and visual
cycle components on the rate of hydrolysis of rhodopsin chromophore in knockout mouse models. Using the
methods described in Aim 2, we will characterize the rate of Schiff base hydrolysis in Arr1-/-, Grk1-/-, Abca4-/-,
and Rdh8-/- mice, providing new insights into how light and dark adaptation are modulated by
phototransduction and visual cycle proteins. 4) Characterize the molecular architecture of rhodopsin
complexes with lipids and small molecules using native mass spectrometry. Using the native MS technique, we
will quantify phospholipids that associate with rhodopsin in its various activation states. We will also validate
the pharmacodynamics and pharmacokinetics of small molecule therapeutic candidates in vivo. We believe the
information gleaned from these studies will enhance our understanding of retinal diseases at the molecular
level and enable the development of novel strategies for their treatment.
摘要:视色素是人类视觉体验的起点,具有重要的生理意义,
并且也受到视网膜疾病的影响。因此,许多研究工作致力于
描述它们的结构-功能关系。尽管作出了这些努力,
了解视觉色素光化学和信号特性。对这一基本视觉的了解
生理学对于在开发相关视网膜病的治疗方面取得加速进展是必要的。在
所有视色素的核心是一种视黄醛发色团,
吸收适当波长的光子。这种复杂的反应,通过几个过程进行,
光中间体,触发光刺激传播到一个光刺激所必需的构象变化。
生化反应这种光活化过程以水解和释放视黄醇结束,
是受体光敏状态更新所必需的,因此是连续视觉功能所必需的。基本
关于视黄醇水解的受体结构、机制和调节剂仍存在问题
Schiff碱和小分子治疗候选物的相互作用模式。
在这里,我们将追求四个具体目标,这些目标采用我们相信能够实现的新开发的工具和方法
克服了以前无法克服的实验挑战。1)视紫红质结构解析
由纳米抗体稳定的光中间体。使用一系列新的骆驼抗体,
视紫红质光循环,我们将进行详细的结构-功能表征的变视紫红质
中间体的2)确定视紫红质和视锥细胞的视黄醛发色团的水解动力学
天然膜中的视蛋白色素。我们开发了一种新的基于质谱的方法,
首次直接检测天然膜中视色素的视网膜共轭状态;我们将
用这种方法来确定关键的速率常数必须模拟视觉色素之间的相互作用,
漂白周期和再生视觉周期。3)评估细胞溶质效应物和视觉
周期组分对基因敲除小鼠模型中视紫红质发色团水解速率的影响。使用
目的2中描述的方法,我们将表征Arr 1-/-,Grk 1-/-,Abca 4-/-,
和Rdh 8-/-小鼠,提供了新的见解,如何光和暗适应调制的
光转导和视觉周期蛋白。4)表征视紫红质的分子结构
与脂质和小分子的复合物。使用原生MS技术,我们
将量化与视紫红质在其各种激活状态下相关的磷脂。我们还将验证
体内小分子治疗候选物的药效学和药代动力学。我们相信
从这些研究中收集的信息将增强我们对视网膜疾病的分子水平的理解。
水平,并使其治疗的新策略的发展。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Philip David Kiser其他文献
Philip David Kiser的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Philip David Kiser', 18)}}的其他基金
Modulation of retinoid reactivity and pathological signaling in retinal therapeutics
视网膜治疗中类维生素A反应性和病理信号的调节
- 批准号:
9891782 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
Modulation of retinoid reactivity and pathological signaling in retinal therapeutics
视网膜治疗中类维生素A反应性和病理信号的调节
- 批准号:
10454758 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
Modulation of retinoid reactivity and pathological signaling in retinal therapeutics
视网膜治疗中类维生素A反应性和病理信号的调节
- 批准号:
10618853 - 财政年份:2020
- 资助金额:
$ 48.08万 - 项目类别:
Studies on visual cycles and their relevance to age-related macular degeneration
视觉周期及其与年龄相关性黄斑变性的相关性研究
- 批准号:
9916594 - 财政年份:2015
- 资助金额:
$ 48.08万 - 项目类别:
Studies on visual cycles and their relevance to age-related macular degeneration
视觉周期及其与年龄相关性黄斑变性的相关性研究
- 批准号:
9254423 - 财政年份:2015
- 资助金额:
$ 48.08万 - 项目类别:
Studies on visual cycles and their relevance to age-related macular degeneration
视觉周期及其与年龄相关性黄斑变性的相关性研究
- 批准号:
8921484 - 财政年份:2015
- 资助金额:
$ 48.08万 - 项目类别:
相似海外基金
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
- 批准号:
NE/Y000080/1 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Research Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328975 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Continuing Grant
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
- 批准号:
2400967 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328973 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Continuing Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
- 批准号:
10112700 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328972 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332916 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332917 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328974 - 财政年份:2024
- 资助金额:
$ 48.08万 - 项目类别:
Continuing Grant
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
- 批准号:
23H01186 - 财政年份:2023
- 资助金额:
$ 48.08万 - 项目类别:
Grant-in-Aid for Scientific Research (B)