Changes in L-type calcium channels during aging in the heart's pacemaker

心脏起搏器衰老过程中L型钙通道的变化

• 批准号: 10003436
• 负责人: Claudia Marcela Moreno
• 金额: $ 24.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10003436
• 关键词: Academic Training; Academic skills; Action Potentials; Affect; Age; Aging; Animals; Artificial cardiac pacemaker; Automobile Driving; Award; Calcium; Calcium Channel; Calcium Signaling; Cardiac; Cells; Complex; Coupled; Coupling; Developed Countries; Developing Countries; Disease; Electrophysiology (science); Environment; Exhibits; Failure; Family; Fostering; Foundations; Frequencies; Functional disorder; Gated Ion Channel; Goals; Heart; Heart Atrium; Heart Diseases; Heterogeneity; Hippocampus (Brain); Human; Ice; Image; Impairment; Implant; Incidence; Ion Channel; Ion Channel Gating; Ions; L-Type Calcium Channels; Life Expectancy; Longevity; Maps; Memory; Mentors; Microscopy; Molecular; Morphology; Mus; Muscle Cells; Mutant Strains Mice; Natural regeneration; Neurons; Pacemakers; Pattern; Peripheral; Phase; Physiology; Probability; Proteins; RNA Splicing; Research; Research Personnel; Resolution; Risk Factors; Role; Sick Sinus Syndrome; Sinoatrial Node; Structure; System; Technical Expertise; Techniques; Testing; Training; Translating; United States; Variant; Ventricular; Work; base; biophysical properties; career; career development; experimental study; heart rhythm; implantation; innovation; loss of function mutation; mRNA Expression; member; nodal myocyte; tool; voltage

Project Summary Rather than being considered as another phase of the lifespan, aging is now considered a major risk factor for heart diseases. One of these age-triggered diseases is the dysfunction of the natural pacemaker of the heart, the sinoatrial node (SAN). SAN dysfunction is the cause of 50% of the over 200.000 artificial pacemakers implanted every year in the US. SAN pacemaking function depends on the calcium signaling sustained by voltage-gated ion channels and the internal calcium stores. The long-term of my scientific career is to understand how aging remodels calcium signaling in the heart and how this relates with the onset of heart diseases. This K99/R00 proposal is the starting point, where I will determine how aging changes the expression and distribution of voltage gated L-type calcium channels. Despite that L-type calcium channels are the channels that sustain the action potential in SAN cells, the changes that these channels undergo during aging are poorly explored. This proposal is divided in two phases: the training K99 phase will focus on the study of the coupling of L-type calcium channels, its role in the pacemaking and how it is affected by aging. This channel coupling is a new mechanism of calcium facilitation that I discovered in hippocampal neurons and that have not been studied in the SAN. During the training phase I will also build technical and academic skills on aging and cardiac physiology. The independent R00 phase will focus on how aging changes the expression, distribution and function of L-type calcium channels. For this part I will take advantage of my previous training and expertise on the study of CaV1.3 channels. I will use electrophysiology to characterize the biophysical properties of the L-type calcium channels in young and old mice. I will use mutant mice strains (CaV1.3-/- and CaV1.2DHPins) to dissect the components of the L-type calcium current and find if aging regulates them differentially. In addition, I will use expansion microscopy and super-resolution imaging to generate maps of the change in the expression and distribution of CaV1.2 and CaV1.3 channels in the SAN during aging. This tool will be useful for further studies in the remodeling of protein in the SAN during aging. Together these results will serve as the foundation of my first R01 and will launch the beginning of my independent research career. For a successful transition to the independence I will count with the mentoring of a team of experts in cardiac and aging physiology, including Dr. Fernando Santana, Dr. Edward Lakatta, Dr. Nipavan Chiamvimonvat and Dr. Donald Bers. They will follow very close my experimental and academic training and help me to establish my career development strategies. The diverse array of expertise and the highly interactive scientific environment at UC Davis is particularly well-suited to foster and support this proposal. The K99/R00 award constitutes a unique opportunity for my advance in the academic track. It will help me to consolidate an innovative niche on the study of the aging of calcium signaling and provide me with the necessary academic and technical training to launch my career as an independent investigator.

项目摘要 现在，衰老被认为是寿命的另一个阶段，而是被认为是主要危险因素 心脏病。这些年龄触发的疾病之一是心脏天然起搏器的功能障碍， Sinotrial节点（SAN）。 SAN功能障碍是超过200.000个人工起搏器的50％的原因 每年在美国植入。 San Pacemaking功能取决于由 电压门控离子通道和内部钙存储。我科学职业的长期是 了解衰老如何在心脏中重塑钙信号，以及与心脏的开始如何关系 疾病。此K99/R00建议是起点，我将确定衰老如何改变 电压门控L型钙通道的表达和分布。尽管L型钙通道是 维持SAN细胞动作潜力的渠道，这些渠道在 衰老的探索很差。该建议分为两个阶段：培训K99阶段将重点放在 研究L型钙通道的偶联，其在起搏器中的作用以及如何受老化的影响。 该通道耦合是我在海马神经元和 尚未在SAN进行研究。在培训阶段，我还将建立技术和学术技能 关于衰老和心脏生理学。独立的R00阶段将集中于衰老如何改变表达式， L型钙通道的分布和功能。对于这一部分，我将利用我以前的培训 和研究CAV1.3渠道的专业知识。我将使用电生理学来表征生物物理 L型钙通道的特性在年轻小鼠和老鼠中。我将使用突变小鼠菌株（Cav1.3 - / - 和 cav1.2dhpins）剖析L型钙电流的成分，并发现衰老是否在调节它们 差异。此外，我将使用膨胀显微镜和超分辨率成像来生成地图 衰老期间，SAN中Cav1.2和Cav1.3通道的表达和分布变化。这个工具 对于在衰老过程中对SAN蛋白质重塑的进一步研究将是有用的。这些结果在一起 将作为我第一个R01的基础，并将启动我独立研究生涯的开始。 为了成功过渡到独立性，我将在心脏专家团队的指导下算 和老化的生理学，包括Fernando Santana博士，Edward Lakatta博士，Nipavan Chiamvimonvat博士和 唐纳德·贝尔斯博士。他们将遵循我的实验和学术培训，并帮助我建立 我的职业发展策略。各种各样的专业知识和高度互动的科学 加州大学戴维斯分校的环境特别适合培养和支持这一建议。 K99/R00奖 在学术轨道上，我的进步构成了一个独特的机会。这将帮助我合并 创新的利基市场研究钙信号的衰老，并为我提供必要的学术 和技术培训以启动我作为独立调查员的职业。