In human embryos, the primary subdivisions of the brain (forebrain, midbrain, and hindbrain) are formed by the fourth week of gestation. During this time, the primitive eyes (optic vesicles) emerge as protrusions from the forebrain. The forms of these organs are highly conserved. Abnormalities in size and shape of the early brain are known to cause serious neurological disorders such as anencephaly, hydrocephalus, autism, and schizophrenia, while improper eye morphogenesis can cause coloboma and microphthalmia, leading to severe visual impairment. Prevention and treatment of these maladies requires understanding of their root cause. While much is now known about the molecular and genetic factors that regulate brain and eye development, the mechanical processes that actually create these structures remain poorly understood. The main objective of this proposed research is to determine the morphogenetic mechanisms that shape the early embryonic brain and eye.
The specific aims are the following: (1) Determine the mechanisms that drive growth and morphogenesis of the developing brain vesicles. (2) Determine the mechanisms that drive growth and morphogenesis of the optic vesicle before the optic cup forms. (3) Determine the mechanisms that drive invagination and shaping of the optic cup. To accomplish these aims, we will integrate computational modeling with quantitative experimental measurements. The models are based on fundamental engineering theories of nonlinear solid mechanics. The experiments, to be conducted on chick and mouse embryos, will employ high-resolution optical coherence tomography (OCT) and fluorescence imaging to measure changes in global and local geometry (e.g., curvature and wall strains) and microstructure (e.g., actin distribution), microdissection to determine and perturb tissue stress, drug exposure and genetic knockouts to perturb cellular function, and measurements of embryonic cerebrospinal fluid pressure and regional mechanical properties. This project will provide important new insights into the morphogenetic mechanisms of brain and eye development.

Public Health Relevance

Abnormalities in size and shape of the early brain are known to cause serious neurological disorders such as anencephaly, hydrocephalus, autism, and schizophrenia, while improper eye development can cause visual impairment. Prevention and treatment of these maladies requires understanding their root cause. This project will provide important new understanding of the morphogenetic mechanisms that create the embryonic brain and eye.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS070918-03
Application #
8309255
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Riddle, Robert D
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
Washington University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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