Mechanisms of human appendicular and cardiovascular comorbidities: An analysis of heterogeneity and lineage trajectories of the lateral plate mesoderm

人类四肢和心血管合并症的机制：侧板中胚层的异质性和谱系轨迹分析

• 批准号: 10642590
• 负责人: Robert L Lalonde
• 金额: $ 9.97万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642590
• 关键词: ALDH1A2 gene; Adult; Advisory Committees; Affect; Bar Codes; Birth; Blood Vessels; Branchial arch structure; CRISPR/Cas technology; Cardiac; Cardiovascular system; Cell Lineage; Cells; Clinical Management; Collaborations; Communication; Complex; Congenital Abnormality; Data; Defect; Development; Development Plans; Developmental Biology; Diagnosis; Diagnostic; Disease; Educational process of instructing; Embryo; Experimental Designs; Fibroblast Growth Factor; Forelimb; GATA4 gene; Genes; Goals; Health; Heart; Heart Abnormalities; Heterogeneity; Human; Image; Individual; Institution; Joints; Label; Lateral; Light; Limb Development; Limb structure; Link; Lung; Medical; Mentors; Mentorship; Mesoderm; Microscopy; Modeling; Mutagenesis; Mutation; Nature; Operative Surgical Procedures; Organ; Patients; Pattern; Pectoral; Phase; Phenotype; Population; Research; Research Personnel; Research Proposals; Resources; Severities; Signal Pathway; Signal Transduction; Skeleton; Specific qualifier value; Structure; Symptoms; Testing; Tissues; Training; Transgenic Organisms; Work; Writing; Zebrafish; body system; cardiogenesis; career; career development; cell type; comorbidity; disease phenotype; experimental study; fundamental research; genetic approach; genome sequencing; human disease; improved; insight; lung development; model organism; pediatric department; progenitor; single-cell RNA sequencing; stem cells; success; supportive environment; therapeutic development; transcriptome; transcriptomics; treatment strategy; whole genome

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.

人类疾病很少局限于单个组织或器官，而是呈现出一系列的