Delineating the Genetic Susceptibility of Smoking-Induced Vascular Dysfunction

描述吸烟引起的血管功能障碍的遗传易感性

• 批准号: 10852366
• 负责人: Hongchao Guo
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10852366
• 关键词: Advisory Committees; Agonist; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Asthma; Atherosclerosis; Bioinformatics; Biological Assay; Biological Markers; Biological Models; Biology; Biometry; Blood Vessels; CASP1 gene; CRISPR interference; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Career Mobility; Cell Adhesion; Cell Line; Cell Survival; Cell model; Cellular biology; Cessation of life; Clinic; Committee Members; Complex; Development; Diagnosis; Disease model; Drug Screening; Endothelial Cells; Environment; Environmental Health; Environmental Risk Factor; Exhibits; Female; Functional disorder; Genetic; Genetic Predisposition to Disease; Genetic Risk; Goals; Grant; Health; High-Throughput RNA Sequencing; Human; Hypersensitivity; IL18 gene; Immune System Diseases; Immunology; Individual; Induction of Apoptosis; Inflammation; Interleukin-1 beta; Knowledge; Mediating; Mentors; Mentorship; Modification; Molecular; Molecular Analysis; Nicotine; Nicotine Dependence; Nicotinic Receptors; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Population; Positioning Attribute; Predisposition; Program Development; Reactive Oxygen Species; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Risk; Role; Signal Pathway; Smoke; Smoking; Stress; Structure; Study models; Techniques; Technology; Testing; Tobacco; Tobacco smoke; Training; Tubular formation; United States; Universities; Variant; Vascular Diseases; Work; aerosolized; cardiovascular risk factor; career; career development; cytokine; drug discovery; extracellular; genetic variant; induced pluripotent stem cell; inflammatory modulation; inhibitor; insight; male; meetings; nicotine exposure; novel; patient stratification; pollutant; prevent; programs; protective effect; risk variant; screening; small molecule; stem cells; transcriptome; transcriptome sequencing

PROJECT SUMMARY This proposal describes a five-year career development program to prepare Dr. Hongchao Guo for a career as an independent investigator. This program will build on Dr. Guo’s background as a molecular stem cell biologist by providing him expertise in bioinformatics, secretomics, and drug discovery techniques, and knowledge on environmental health, immunology and cardiovascular biology to advance our understanding on how genetic differences in individuals contribute to their susceptibility to smoking-related cardiovascular disease. Dr. Guo will be mentored by Dr. Joseph Wu, Director of Stanford Cardiovascular Institute, who is an expert in cardiovascular disease modeling using induced pluripotent stem cells (iPSCs). In addition, Dr. Guo will be co-mentored by Dr. Kari Nadeau, Director of the Sean N. Parker Center for Allergy and Asthma Research at Stanford University, who is an expert in studying aerosolized pollutants including tobacco smoke on the development of immune dysfunction in primary immune disease, allergy and asthma. The K99 phase of Dr. Guo’s training will consist of structured mentorship by the primary mentor and co-mentor, close interactions with collaborators, complementary meeting with advisory committee members, a provocative research project, and a tailored program for career development and transition. In Dr. Guo’s previous works, he has recapitulated key features of nicotine-induced vascular dysfunction in patients using patient-specific iPSC-derived endothelial cell (iPSC- EC). He has also shown that genetic variants in nicotinic acetylcholine receptor exacerbated nicotine-induced EC dysfunction via increasing inflammation cytokines expression and apoptosis, which allow for analysis of the molecular mechanism in iPSC-EC model with a level of depth and resolution never before achieved. With the current advancement in high-throughput RNA sequencing and the cutting-edge secretomics and drug screening technologies, Dr. Guo is in a unique position to stratify the patient risk of genetic variants in nicotinic receptors for smoking-induced vascular diseases, and to study the potential mechanisms, with the ultimate goal to discover biomarkers and precise treatment for cardiovascular diseases and risks. In the K99 phase, Dr. Guo will generate and characterize patient-specific and isogenic iPSC-EC models for studying the susceptibility of three different nAChR variants to nicotine-induced vascular dysfunction (Aim 1). With the platform, Dr. Guo will then integrate high-throughput RNA sequencing and cutting-edge secretomics technologies to define the key molecular basis and secretomic biomarkers for the risk of these variants to smoking-mediated vascular diseases (Aim 2). In the R00 phase, Dr. Guo will develop a screening platform to examine the beneficial effect of anti-inflammatory drugs and screen mechanism-oriented small molecules in iPSC-EC carrying these risk variants (Aim 3). Collectively, Dr. Guo’s proposed work will create a valuable platform to evaluate the risk of these variants to smoking-related vascular disease and to reveal the molecular mechanisms and biomarkers. Additionally, this work will lead to studying of mechanism-oriented treatment, which will be carried out by Dr. Guo as an independent investigator.

项目摘要 该建议描述了一项为期五年的职业发展计划，旨在为Hongchao Guo博士做好职业的准备 独立研究者。该程序将以Guo博士为背景作为分子干细胞生物学家的背景 通过为他提供生物信息学，秘密学和药物发现技术的专业知识，以及有关 环境健康，免疫学和心血管生物学，以促进我们对遗传的理解 个体的差异有助于他们对吸烟相关的心血管疾病的敏感性。 Guo Will博士 由斯坦福心血管研究所主任约瑟夫·吴（Joseph Wu）博士指导，他是心血管的专家 使用诱导多能干细胞（IPSC）进行疾病建模。此外，Guo博士将由博士授予。 斯坦福大学Sean N. Parker过敏和哮喘研究中心的主任Kari Nadeau， 谁是研究雾化污染物（包括烟草烟雾）的专家 原发性免疫疾病，过敏和哮喘的功能障碍。 Guo博士培训的K99阶段将包括 主要的心理和同事的结构化精神训练，与合作者的紧密互动， 与咨询委员会成员，一个挑衅性研究项目和量身定制的咨询委员会成员会面 职业发展和过渡计划。在Guo博士以前的作品中，他概括了关键功能 使用患者特异性IPSC衍生的内皮细胞（IPSC- EC）。他还表明，烟碱乙酰胆碱受体中的遗传变异加剧了尼古丁诱导的 EC功能障碍通过增加炎症细胞因子表达和凋亡，这可以分析 IPSC-EC模型中具有深度和分辨率水平的分子机制。与 当前的高通量RNA测序以及尖端的秘密和药物筛查的进步 技术，Guo博士处于独特的位置，可以分层烟碱受体中遗传变异的风险 吸烟引起的血管疾病并研究潜在机制，最终目标是发现 生物标志物和心血管疾病和风险的精确治疗。在K99阶段，Guo博士将产生 并表征患者特异性和同基因IPSC-EC模型，用于研究三种不同的易感性 NACHR变体具有尼古丁诱导的血管功能障碍（AIM 1）。使用该平台，郭博士将整合 高通量RNA测序和尖端的秘密细胞技术来定义关键分子基础 以及秘密生物标志物，出现这些变体对吸烟介导的血管疾病的风险（AIM 2）。在 R00阶段，郭博士将开发一个筛选平台，以检查抗炎药的有益效果 以及带有这些风险变体的IPSC-EC中的面向筛查机理的小分子（AIM 3）。共同 Guo博士的拟议工作将创建一个有价值的平台，以评估与吸烟有关的这些变体的风险 血管疾病并揭示分子机制和生物标志物。此外，这项工作将导致 研究以机制为导向的治疗，该治疗将由Guo博士作为独立研究者进行。