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Principal Investigator: Hongchao Guo
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $249,000
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <Active Oxygen><Advisory Committees><Agonist><Allergy><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatory Effect><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 1><Assay><Asthma><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Beta Proprotein Interleukin 1><Bio-Informatics><Bioassay><Bioinformatics><Biologic Models><Biological Assay><Biological Markers><Biological Models><Biology><Biometrics><Biometry><Biostatistics><Blood Vessels><Bronchial Asthma><CASP-1><CASP1><CASP1 gene><CRISPR approach><CRISPR based approach><CRISPR interference><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR-dCas9-mediated repression><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CRISPR/dCas9 interference><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRi><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Career Mobility><Cas nuclease technology><Caspase-1><Caspase-1 Gene><Cell Adhesion><Cell Line><Cell Survival><Cell Viability><Cell model><CellLine><Cellular Adhesion><Cellular biology><Cellular model><Cessation of life><Clinic><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats interference><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Committee Members><Complex><Death><Development><Diagnosis><Drug Screening><Drug Therapy><Drugs><Dysfunction><Endothelial Cells><Environment><Environmental Factor><Environmental Health><Environmental Health Science><Environmental Risk Factor><Exhibits><Female><Functional disorder><Gene variant><Genetic><Genetic Predisposition><Genetic Predisposition to Disease><Genetic Risk><Genetic Susceptibility><Genetic propensity><Goals><Grant><Health><Heart Vascular><High-Throughput RNA Sequencing><Human><Hypersensitivity><ICE Protease><IFN-Gamma-Inducing Factor Gene><IFN-gamma-Inducing Factor><IGIF><IGIF Gene><IL-1 Gamma><IL-1 Gamma Gene><IL-1 beta><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1 β><IL-1-b><IL-18><IL-18 Gene><IL-1BC><IL-1b Converting Enzyme><IL-1g><IL-1g Gene><IL-1β><IL1-Beta><IL1-β><IL18><IL18 Protein><IL18 gene><IL1B Protein><IL1B-Convertase><IL1BC><IL1BCE><IL1F2><IL1F4><IL1F4 Gene><IL1β><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunology><Individual><Induction of Apoptosis><Inflammation><Inherited Predisposition><Inherited Susceptibility><Interferon-Gamma-Inducing Factor Gene><Interferon-gamma-Inducing Factor><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin 18 (Interferon-Gamma-Inducing Factor)><Interleukin 18 (Interferon-Gamma-Inducing Factor) Gene><Interleukin 18 Proprotein><Interleukin 18 Proprotein Gene><Interleukin 1beta><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Interleukin-1 Gamma><Interleukin-1 Gamma Gene><Interleukin-1 beta><Interleukin-18><Interleukin-18 Precursor><Interleukin-18 Precursor Gene><Interleukin-1β><Investigators><Knowledge><MGC12320><MGC12320 Gene><Mediating><Medication><Mentors><Mentorship><Model System><Modern Man><Modification><Molecular><Molecular Analysis><Nicotine><Nicotine Dependence><Nicotinic Acetylcholine Receptors><Nicotinic Receptors><Oxygen Radicals><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacotherapy><Phase><Physiopathology><Population><Position><Positioning Attribute><Predisposition><Preinterleukin 1 Beta><Pro-Oxidants><Progenitor Cells><Program Development><Programmed Cell Death><R-Series Research Projects><R01 Mechanism><R01 Program><RNA Seq><RNA sequencing><RNAseq><Reactive Oxygen Species><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resolution><Risk><Risk-associated variant><Role><Signal Pathway><Smoke><Smoking><Strains Cell Lines><Stress><Structure><Study models><Susceptibility><Task Forces><Techniques><Technology><Testing><Tobacco><Tobacco smoke><Training><Tubular><Tubular formation><United States><Universities><Variant><Variation><Vascular Diseases><Vascular Disorder><Work><advisory team><aerosolized><allele variant><allelic variant><anti-inflammatory effect><atheromatosis><atherosclerotic disease><atherosclerotic vascular disease><bio-markers><biologic marker><biomarker><blood vessel disorder><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><career><career advancement><career development><career transition><cell biology><circulatory system><cultured cell line><cytokine><developmental><disease model><disorder model><drug discovery><drug treatment><drug/agent><environmental risk><exposure to nicotine><extracellular><genetic etiology><genetic mechanism of disease><genetic variant><genetic vulnerability><genetically predisposed><genomic variant><global gene expression><global transcription profile><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><iPS><iPSC><iPSCs><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><induced pluripotent stem cells derived from patients><induced pluripotent stem cells from patients><inducible pluripotent stem cell><inflammatory modulation><inhibitor><insight><male><meeting><meetings><nicotine addiction><nicotine dependent><nicotine exposure><novel><pathophysiology><pathway><patient derived human iPS><patient derived human iPSC><patient derived human induced pluripotent stem cell><patient derived iPS><patient derived iPSC><patient derived induced pluripotent cells><patient derived induced pluripotent stem cells><patient stratification><patient-derived pluripotent stem cells><pollutant><prevent><preventing><programs><protective effect><repressing CRISPR-dCas9 system><resolutions><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><screening><screenings><small molecule><social role><stem cells><stratified patient><transcriptome><transcriptome sequencing><transcriptomic sequencing><vascular><vascular dysfunction><vasculopathy>