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

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:视觉色素启动了人类的视觉体验,具有重要的生理意义。

项目成果

期刊论文数量(0)
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Philip David Kiser其他文献

Philip David Kiser的其他文献

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{{ truncateString('Philip David Kiser', 18)}}的其他基金

Chemical Biology of the Visual Pigments
视觉颜料的化学生物学
  • 批准号:
    10849462
  • 财政年份:
    2023
  • 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:
    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:
Retinoids in Vision
视黄醇在视觉中的作用
  • 批准号:
    9762929
  • 财政年份:
    1992
  • 资助金额:
    $ 48.08万
  • 项目类别:

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