[DP2] Defining mechanisms of resilience in mammalian cardiogenesis
Ente: National Heart Lung and Blood Institute
Scadenza: 2031-05-31
Importo max: $761,897
Paese: US
Descrizione
PROJECT ABSTRACT
During animal development, one single cell divides to generate every cell type in the body. This process
is incredibly complex, highly coordinated, but perhaps most remarkable, it is very resilient. For example,
during development, large numbers of cells can be removed or added to the embryo, and the embryo is
able to compensate for errors, correct itself, and resume normal development to produce healthy
offspring. Despite these striking phenomena, the basic mechanisms and cellular players that underlie
embryonic plasticity and resilience remain unknown. This gap in knowledge largely stems from the
historical lack of tools needed to precisely measure cellular responses and trace lineage trajectories at
high-resolution in vivo. In this project, we will combine classical embryological approaches with powerful
cutting-edge tools to define the mechanisms and cell populations responsible for governing resilience in
the mammalian embryonic heart. Cardiogenesis represents an ideal model for studying embryo resilience
as it is a highly complex process that involves contributions from multiple migrating pools of progenitor
cells, and it is also highly resilient to cell loss. Therefore, studying how the embryonic heart maintains
robust development despite perturbations will provide fundamental insights into the principles of
developmental resilience that can be leveraged to enhance tissue resilience in broader contexts. Towards
our aim, we will first use next-generation cellular barcoding-based lineage tracing approaches to build a
high-resolution, spatially-resolved fate map of cardiac formation during normal, unperturbed
development. Next, we will develop new genetic approaches for inducible, in vivo cell ablation to define
the cell lineages that re-populate the heart following injury and to determine the extent of lineage plasticity
during heart development. Finally, we will perform single-cell ‘omics analyses and embryo culture assays
to determine the earliest responses to cell loss in the developing heart. Together, this work will enable us
to answer major, long-standing questions in developmental biology and transform our basic
understanding of fate commitment and plasticity. Furthermore, in uncovering mechanisms governing
tissue resilience during embryonic development, we will be a step closer to harnessing these
mechanisms to increase tissue resilience in broader contexts. This knowledge is likely to have
applicability to diverse areas of biomedical research, from understanding the etiology of developmental
defects and targeting resilience in diseases such as cancer, to improving regeneration outcomes
following injury in adulthood.
Istituzione: STANFORD UNIVERSITY
PI: Sarah Bowling
Progetto: 1DP2HL193397-01
Settori: National Heart Lung and Blood Institute
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