Bridging Across Scales to Model Cone Phototransduction

跨尺度桥接锥体光转导模型

• 批准号: 1812601
• 负责人: Emmanuele DiBenedetto
• 金额: $ 44.92万
• 依托单位: Vanderbilt University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1812601&HistoricalAwards=false
• 关键词: Bridging; Across; Scales; Model; Cone

Rods and cones in the retina mediate vision. While rods detect white light, cones are designed for color vision. Their role is crucial in high acuity vision as underscored by their loss in age-related macular degeneration leading to blindness. A common feature of these cells is their intricate geometrical structure, consisting of about one thousand thin pancake-like folds (discs) through which light is transformed into electrical pulses (phototransduction) for the brain to "see." Light is captured by receptors/pigments residing on these folds, and transformed into a current between interior and exterior of these cells, by a cascade of biochemical steps. These steps involve amplifiers of the light signal (transducers and effectors) and carriers of the signal (second messengers) diffusing within these folds. A mathematical understanding of these processes is complicated by the numbers of these folds (about one thousand) and their thickness (a few nanometers). The mathematical theory of homogenization seeks to replace the complex geometry with a simpler, cylindrical structure while preserving all the biochemical and biophysical functions of the original system. The transduction cascade must be reliable/stable for consistency of visual perception, and sources of instability and stabilizing mechanisms in the cascade can be broken down and analyzed via mathematical modeling. This interdisciplinary investigation involves mathematics (homogenization), computational sciences (finite element code writing), biochemistry (activation/deactivation cascades), and physiology (diffusion of second messengers). The project involves students and postdoctoral trainees and will be disseminated through training courses and seminars. This research is funded jointly by the Division of Mathematical Sciences Mathematical Biology Program and the Division of Integrative Organismal Systems Physiological Mechanisms and Biomechanics Program. Cones capture light in the red, blue and green wavelength, and as such, besides their geometrical shape, their biochemical and biophysical functions are different than rods. In particular they never saturate, they have a faster and smaller response, they are little sensitive to dim light and have a faster deactivation. The photoresponse is generated by diffusion of the second messengers calcium and CGMP in the cytoplasm within the lipidic discs. To overcame the intricate geometry of the discs (about a thousand, each a few nanometers thick) we propose an homogenization process, by which the number of discs goes to infinity and their thickness goes to zero, while the volume available for diffusion remains unchanged, and the biochemical and biophysical functions are preserved in the limit. The limiting "homogenized" cone becomes cylinder-like, with no discs, and the diffusion process is separated into interior and boundary diffusion on the homogenized domain. The activation/deactivation process is modeled by a continuous-time Markov chain tracking the various steps of the cascade. The resulting model is hybrid as it contains a deterministic part (homogenized diffusion of the second messengers) with a random input (stochastic steps of the activation/deactivation cascade). This permits one to analyze the mechanism by which random deactivation events turn into a stable photoresponse, and identify the causes of variability and variability suppression. A database of parameters will be created to populate the model and effect numerical simulations to be compared with experimental data, including lack of saturation, low sensitivity and faster deactivation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

视网膜中的视杆细胞和视锥细胞调节视觉。 视杆细胞检测白色光，而视锥细胞是为颜色视觉而设计的。他们的作用是至关重要的高敏锐度的视力，强调了他们的损失，年龄相关性黄斑变性导致失明。 这些细胞的一个共同特征是它们复杂的几何结构，由大约1000个薄煎饼状折叠（圆盘）组成，通过这些折叠，光被转化为电脉冲（光传导），供大脑“看到”。“光被驻留在这些褶皱上的受体/色素捕获，并通过一系列生化步骤转化为这些细胞内部和外部之间的电流。这些步骤涉及光信号的放大器（转换器和效应器）和信号的载体（第二信使）在这些褶皱内扩散。对这些过程的数学理解由于这些折叠的数量（大约一千）和它们的厚度（几纳米）而变得复杂。均质化的数学理论试图用更简单的圆柱形结构取代复杂的几何形状，同时保留原始系统的所有生物化学和生物物理功能。为了视觉感知的一致性，转导级联必须是可靠/稳定的，并且级联中的不稳定性和稳定机制的来源可以通过数学建模来分解和分析。 这种跨学科的研究涉及数学（均质化），计算科学（有限元代码编写），生物化学（激活/失活级联）和生理学（第二信使的扩散）。该项目涉及学生和博士后受训人员，并将通过培训班和研讨会加以传播。本研究由数学科学部、数学生物学计划部和综合有机系统、生理机制和生物力学计划部联合资助。 视锥细胞捕获红色、蓝色和绿色波长的光，因此，除了它们的几何形状外，它们的生物化学和生物物理功能与视杆细胞不同。特别是它们永远不会饱和，它们具有更快和更小的响应，它们对昏暗的光几乎不敏感，并且具有更快的失活。 光反应是由第二信使钙和CGMP在椎间盘内的细胞质中扩散产生的。为了克服复杂的几何形状的光盘（约1000，每几纳米厚），我们提出了一个均匀化的过程中，光盘的数量去无穷大，其厚度为零，而体积可用于扩散保持不变，和生化和生物物理功能被保存在极限。 有限的“均匀化”锥成为圆柱状，没有光盘，和扩散过程被分离成内部和边界扩散的均匀化域。的激活/失活过程建模的连续时间马尔可夫链跟踪级联的各个步骤。由此产生的模型是混合的，因为它包含一个确定性的部分（均匀扩散的第二信使）与随机输入（随机步骤的激活/失活级联）。这使得人们可以分析随机失活事件转变为稳定光响应的机制，并确定可变性和可变性抑制的原因。将创建一个参数数据库，以填充模型并进行数值模拟，以便与实验数据进行比较，包括缺乏饱和度，低灵敏度和更快的失活。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Multi-scale, numerical modeling of spatio-temporal signaling in cone phototransduction

• DOI: 10.1371/journal.pone.0219848
• 发表时间: 2019-07-25
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Klaus，Colin;Caruso，Giovanni;DiBenedetto，Emmanuele
• 通讯作者: DiBenedetto，Emmanuele