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We will build predictive regulatory models of neural development to help us understand what goes wrong in neural pathologies. Using our models we will explore why specific groups of motor neurons die in Spinal Muscular Atrophy (SMA), develop clues for therapeutic targets that might help individuals with SMA, and study how stem cells respond to external cues that could lead to methods of programming stem cells for therapies. | |
We propose to further our understanding of the molecular mechanisms that direct
stem cells during neural development with the ultimate goal of enabling stem
cell based regenerative medicine for neurodegenerative diseases. We will study
the etiology of Spinal Muscular Atrophy (SMA) in the context of the mechanisms
that we elucidate with the goal of developing clues to potential therapeutic
targets for this developmental disease. To understand how external cues direct
development, we will elucidate the transcriptional regulatory networks
underlying neural development and represent this understanding in predictive
computational models. Our studies will begin with undifferentiated embryonic
stem (ES) cells, and using protocols that we have pioneered, we will elucidate
the mechanism of ES cell development and fate commitment in specific neuron
subtypes. Our work is structured into three projects. Collaborators at Columbia
University will identify the transcription factors potentially involved in motor neuron
identity, iteratively define transcriptional networks, and characterize the
transcriptional consequences of SMA. Drawing upon these results, collaborators at
the Whitehead Institute will discover how key transcriptional and chromatin regulators
control the gene
expression programs of mouse and human embryonic stem cells and discover how
this regulatory circuitry changes upon differentiation into spinal progenitor
cells and then specific classes of central nervous system cells such as motor
neurons. Using data from both of these projects, collaborators at the
Massachusetts Institute of Technology will build a model
of transcriptional regulation during neural development that integrates
expression data, factor binding data, chromatin data, shRNA knock down data, and
genome sequence in both human and mouse, examine the gene expression
consequences of our SMA model in the context of the deduced regulatory networks,
and explore the validity of the mouse model for human ES cell differentiation.
Collaborators at both Columbia University and the Whitehead Institute will test
the models produced by collaborators at MIT.
Studying the way in which specific groups of motor neurons in the
spinal cord develop to innervate specific muscles is central to
understanding how precise control of breathing and movement is
achieved. These studies will provide clues for understanding why
specific groups of motor neurons degenerate and die in patients
with diseases such as spinal muscular atrophy (SMA). This project
will identify molecular mechanisms involved both in normal
development and pathologic degeneration of this important
neuronal population.
Considerable progress has been made in defining the transcriptional
events that control the stepwise differentiation of unspecified neural
precursors into motor neurons that innervate specific muscle targets.
Despite these advances, much remains to be learned of the transcriptional
regulatory network that subtends this process. Based on the ability
to generate homogeneous preparations of specific motor neuron subtypes
from ES cells, this project will take a global approach to defining
transcriptional differences between motor neurons and other spinal neurons.
Transcription factors identified will then be used to identify target
genes and thereby iteratively define transcriptional networks. The work
is structured around three aims.
Our goal is to discover how key transcriptional and chromatin
regulators control the gene expression programs of mouse and human
embryonic stem cells and to discover how this regulatory circuitry
changes upon differentiation into spinal progenitor cells and then
specific classes of central nervous system cells such as motor
neurons. This knowledge will enable us to define the transcriptional
regulatory processes that control a cells progress to its terminally
differentiated state, and may provide new insights into the means by which
embryonic stem (ES) cells can be programmed for therapeutic purposes. To
accomplish this, the specific aims of the proposal are:
We will build predictive regulatory models of neural development to
help us understand what goes wrong in neural pathologies. Using our
models we will explore why motor neurons die in Spinal Muscular
Atrophy (SMA), develop clues for therapeutic targets that might help
individuals with SMA, and study how stem cells respond to external
cues that could lead to methods of programming stem cells for therapies.
We will build models of transcriptional regulation that identify at
the molecular level how cells become committed to a particular neural
fate and explore how embryonic stem (ES) cells can be programmed for
therapeutic purposes. We will examine the effect of Survival of
Motor Neuron (SMN) protein deficiency on the resulting regulatory
models and the corresponding etiology of Spinal Muscular Atrophy (SMA).
We will build our models by discovering key elements of the
transcriptional regulatory network that underlie the development of
mouse ES cells into spinal progenitor cells and finally into specific
classes of central nervous system cells such as motor neurons. We
will also examine the same neuronal developmental process in human
ES cells and develop models for studying the conservation between
the mouse and human transcriptional networks in this system.
Our work is structured around three aims.
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