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Diversity Supplement Denzel Deo Omengan

多样性补充剂 Denzel Deo Omengan

基本信息

批准号：
10381108
负责人：
Guo Huang
金额：
$ 3.86万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381108
关键词：
Adult Animals Area Arrhythmia Automobile Driving Basal metabolic rate Biogenesis Biological Assay Biology Birth Cardiac Cardiac Myocytes Cell Cycle Cell Cycle Arrest Cell Cycle Regulation Cessation of life Chemicals Cicatrix Cytokinesis DNA biosynthesis Data Development Diploidy Down-Regulation Endocrine system Evolution Family Dasypodidae Gene Expression Regulation Genes Genetic Growth Heart Heart Block High Prevalence Life Mammals Metabolic Pathway Mitochondria Mole Rats Molecular Mononuclear Mus Muscle Cells Mutant Strains Mice Myocardial Infarction Myrmecophagidae Natural regeneration Neonatal Newborn Infant Newts Nuclear Hormone Receptors Organ Organism Oxidative Stress Pathway interactions Patients Perinatal Pharmacology Phylogenetic Analysis Phylogeny Physiological Ploidies Process Rattus Reactive Oxygen Species Receptor Activation Regenerative capacity Reporting Research Role Signal Transduction Source Spiny Anteater Stimulus Testing Thyroid Function Tests Thyroid Hormones Thyroxine Tissues Up-Regulation Vertebrates Work Zebrafish base cardiac regeneration cardiogenesis comparative experimental study falls functional improvement hemodynamics hormonal signals hormone deficiency in vivo ischemic injury loss of function mouse model myocardial injury neonatal mice novel parent grant postnatal preservation regeneration potential regenerative tool transcriptome transcriptome sequencing

项目摘要

Project Summary/Abstract Most adult mammalian tissues and organs have very limited regenerative potential. In patients with a heart attack, the death and loss of heart muscle cells is irreversible and often results in permanent scarring and potentially life-threatening arrhythmias. In contrast, neonatal mice and adult zebrafish are able to rapidly regenerate their hearts. Genetic lineage-tracing experiments have revealed proliferation of pre-existing cardiomyocytes as the dominant mechanism to generate new muscle cells. However shortly after birth, the majority of cardiomyocytes in most mammalian species undergoes a last round of DNA replication without cytokinesis, become binucleated, and withdraw from the cell cycle. What physiological signals trigger mammalian cardiomyocyte perinatal binucleation and cell cycle arrest, and how these stimuli are differentially regulated in animals with distinct cardiac regenerative potentials are among the most long-standing questions in cardiomyocyte biology. Our preliminary observations from comparative analyses of cardiomyocytes across phylogeny, in vivo chemical screens of candidate pathways, together with functional studies in both mice and zebrafish suggest a critical role of the perinatal changes of endocrine systems in driving cardiomyocyte proliferative and regenerative potential loss in the mammalian heart. In this proposal, we plan to combine a novel cardiomyocyte quantification assay with state-of-art genetic tools to investigate the functions of nuclear hormone receptor activation in regulating cardiomyocyte proliferation during postnatal growth (Aim 1) and heart regeneration following myocardial injury (Aim 2). In addition, we will examine the underpinning cellular and molecular basis, and determine the function of novel downstream target genes in cardiomyocyte cell cycle control through gain- and loss-of-function approaches (Aim 3). Successful completion of the proposed work will thus reveal mechanisms underlying the loss of cardiomyocyte regenerative potential in ontogeny and phylogeny.

项目总结/文摘