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

基本信息

批准号：
10239230
负责人：
Hongchao Guo
金额：
$ 14.14万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10239230
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 Cells 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 Immune System Diseases Immunology Individual Inflammation Inflammatory Institutes Interleukin-1 beta Interleukin-18 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 disorder risk career career development cytokine drug discovery endothelial stem cell extracellular genetic variant induced pluripotent stem cell inhibitor/antagonist insight male meetings nicotine exposure novel patient stratification pollutant prevent programs protective effect receptor risk variant screening small molecule stem cells transcriptome transcriptome sequencing

项目摘要

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.

项目概要该提案描述了一个五年职业发展计划，旨在为郭洪超博士的职业生涯做好准备该项目将建立在郭博士作为分子干细胞生物学家的背景之上。通过为他提供生物信息学、分泌组学和药物发现技术方面的专业知识以及环境健康、免疫学和心血管生物学，以增进我们对遗传机制的理解郭博士认为，个体差异导致他们对吸烟相关的心血管疾病的易感性。师从美国斯坦福心血管研究所所长、心血管领域专家Joseph Wu博士此外，郭博士将得到郭博士的共同指导。卡里·纳多 (Kari Nadeau)，斯坦福大学肖恩·帕克过敏和哮喘研究中心主任，他是研究包括烟草烟雾在内的气溶胶污染物对免疫发展的影响的专家郭博士培训的K99阶段将包括原发性免疫疾病、过敏和哮喘的功能障碍。由主要导师和共同导师进行结构化指导，与合作导师密切互动，与咨询委员会成员的补充会议、一个具有挑战性的研究项目以及量身定制的在郭博士之前的著作中，他概括了职业发展和过渡计划的关键特征。使用患者特异性 iPSC 衍生内皮细胞（iPSC- EC）他还表明，烟碱乙酰胆碱受体的遗传变异加剧了尼古丁诱导的症状。 EC 功能障碍是通过增加炎症细胞因子表达和细胞凋亡来实现的，从而可以分析 iPSC-EC 模型中的分子机制具有前所未有的深度和分辨率。高通量 RNA 测序以及尖端分泌组学和药物筛选的最新进展技术方面，郭博士处于独特的地位，可以对患者烟碱受体遗传变异的风险进行分层针对吸烟引起的血管疾病，并研究其潜在机制，最终目标是发现在K99阶段，郭博士将产生心血管疾病和风险的生物标志物和精准治疗。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 变异导致尼古丁引起的血管功能障碍（目标 1），郭博士将通过该平台进行整合。高通量RNA测序和尖端分泌组学技术来定义关键分子基础以及这些变异与吸烟介导的血管疾病风险的分泌生物标志物（目标 2）。 R00阶段，郭博士将开发筛选平台，检验抗炎药物的有益效果并筛选 iPSC-EC 中携带这些风险变异的机制导向小分子（目标 3）。郭博士提出的工作将创建一个有价值的平台来评估这些变异与吸烟相关的风险此外，这项工作还将揭示血管疾病的分子机制和生物标志物。机制导向治疗的研究，将由郭博士作为独立研究者进行。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deciphering pathogenicity of variants of uncertain significance with CRISPR-edited iPSCs.

使用 CRISPR 编辑的 iPSC 破译意义不确定的变异的致病性。

DOI：
10.1016/j.tig.2021.08.009
发表时间：
2021-12
期刊：
Trends in genetics : TIG
影响因子：
0
作者：
Guo H;Liu L;Nishiga M;Cong L;Wu JC
通讯作者：
Wu JC

Systems analysis of de novo mutations in congenital heart diseases identified a protein network in the hypoplastic left heart syndrome.

对先天性心脏病从头突变的系统分析确定了左心发育不全综合征中的蛋白质网络。

DOI：
10.1016/j.cels.2022.09.001
发表时间：
2022-11-16
期刊：
Cell systems
影响因子：
9.3
作者：
Y. Wang;Xicheng Zhang;C. Lam;Hongchao Guo;Cheng Wang;Sai Zhang;Joseph C. Wu;M. Snyder;Jingjing Li
通讯作者：
Jingjing Li