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Principal Investigator: Robert L Lalonde
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $99,661
Funding agency: National Heart Lung and Blood Institute
Human diseases are seldom confined to individual tissues or organs, but instead present with a spectrum of
comorbidities. A common example includes a group of congenital diseases with linked heart, limb, and lung
defects. Using zebrafish as model, the goal of my research is to uncover how individual causative genes drive
multi-organ comorbidities in the heart, limb, and lung. Understanding the underlying mechanisms will contribute
to the development of therapeutics across disease groups and improve predictive diagnostics of patients with
complex multi-organ diseases. In the adult body, the heart, limb, and lung vasculature seem unrelated at the
structural level, yet share a close developmental origin in the embryo. These structures all derive from
uncommitted lateral plate mesoderm that harbors progenitor cells for numerous organ systems. My overarching
hypothesis posits that the lineages of the heart, limb, and lung blood vessels (cardiopharyngeal vasculature)
derive from a common progenitor population within the lateral plate mesoderm, and form in an interconnected
manner through the action of TBX-FGF and lineage-specific signaling inputs.
In Aim 1, I will test the lineage connection between heart, pectoral fin, and cardiopharyngeal vasculature
using transgenic lineage labeling and CRISPR-Cas9-based barcoding experiments. My work will directly test my
hypothesis that heart, limb, and lung defects are linked by a shared developmental origin of the affected cell
types. In Aim 2, I will functionally test the contribution of TBX-FGF signaling pathways, and lineage-specific
inputs on joint heart, limb, and cardiopharyngeal vasculature lineage patterning. These experiments will test the
impact of shared and lineage-specific signaling perturbation on co-occurrence and severity of heart, pectoral fin,
and cardiopharygneal vasculature defects. Upon completion of my aims I will have tested how shared lineage
origins, and perturbation of shared signaling pathways and lineage-specific inputs, contribute to human diseases
with linked heart, limb, and lung defects.
Altogether, my proposed research aims, my technical training, and my career development plan will provide
the basis for my career goal of becoming an independent investigator at a leading research institution. During
the K99 phase, I will receive mentorship from my mentor Dr. Christian Mosimann and my advisory team, and
technical training from my collaborative team consisting of light sheet microscopy, scRNA-seq experimental
design, and cardiovascular phenotypic analysis. My career development plan will further my training in
intellectual development and collaboration, scientific writing and communication, and mentorship and teaching,
facilitating my transition to an independent investigator during the R00 phase. The section of Developmental
Biology within the Department of Pediatrics at the CU Anschutz Medical Campus is an exceptionally supportive
environment, providing extensive resources that will contribute to my continued academic success and
professional development, facilitating the accomplishment of my career goals.
Terms: <21+ years old><ALDH1A2><ALDH1A2 gene><Adult><Adult Human><Advisory Committees><Affect><Aldehyde Dehydrogenase 1 Family, Member A2 Gene><Bar Codes><Birth><Birth Defects><Blood Vessels><Body System><Body Tissues><Brachydanio rerio><Branchial arch structure><CRISPR approach><CRISPR based approach><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/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cardiac><Cardiac defect><Cardiac development><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Lineage><Cell Signaling><Cells><Clinical Management><Clustered Regularly Interspaced Short Palindromic Repeats approach><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><Collaborations><Communication><Complex><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Defects><Congenital Deformity><Congenital Malformation><DNA Synthesis Factor><Danio rerio><Data><Defect><Development><Development Plans><Developmental Biology><Diagnosis><Diagnostic><Disease><Disorder><Educational process of instructing><Embryo><Embryonic><Endothelial Cell Growth Factor><Experimental Designs><Extremities><FGF><Fibroblast Growth Factor><Fibroblast Growth Factor Gene Family><Fibroblast Growth Regulatory Factor><Forelimb><GATA binding protein 4><GATA4><GATA4 gene><GATA4 transcription factor><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genetics-Mutagenesis><Goals><Health><Heart><Heart Vascular><Heterogeneity><Human><Image><Individual><Institution><Intracellular Communication and Signaling><Investigators><Joints><Label><Lateral><Light><Limb Development><Limb structure><Limbs><Link><Lung><Lung Respiratory System><Medical><Mentors><Mentorship><Mesoderm><Microscopy><Modeling><Modern Man><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Nature><Non-Trunk><Operative Procedures><Operative Surgical Procedures><Organ><Organ System><Parturition><Patients><Pattern><Pectoral><Pharangeal Arch><Phase><Phenotype><Photoradiation><Progenitor Cells><RALDH2 Gene><Research><Research Personnel><Research Proposals><Research Resources><Researchers><Resources><Retinaldehyde-Specific Dehydrogenase Type 2><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skeleton><Specific qualifier value><Specified><Structure><Surgical><Surgical Interventions><Surgical Procedure><Symptoms><Task Forces><Teaching><Testing><Tissues><Training><Transgenic Organisms><Visceral Arches><Work><Writing><Zebra Danio><Zebra Fish><Zebrafish><adulthood><advisory team><aldehyde dehydrogenase 1A2><barcode><biological signal transduction><branchial arch><cardiogenesis><career><career development><cell type><circulatory system><co-morbid><co-morbidity><comorbidity><developmental><disease phenotype><enthusiastic atmosphere><enthusiastic environment><entire genome><experiment><experimental research><experimental study><experiments><full genome><fundamental research><genetic approach><genetic strategy><genome mutation><genome sequencing><global gene expression><global transcription profile><heart defect><heart development><heart formation><human disease><imaging><improved><insight><lung development><model organism><pediatric department><pharyngeal arch><progenitor><progenitor cell population><progenitor population><pulmonary><retinal dehydrogenase II><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skeletons><stem and progenitor cell population><stem cell population><stem cells><success><supportive atmosphere><supportive environment><surgery><therapeutic agent development><therapeutic development><transcriptome><transcriptomics><transgenic><treatment strategy><vascular><whole genome>