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Name of Submitter:
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Clifford Woolf
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Title of proposed idea:
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Transcription factor codes to produce human neuronal subtypes
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What is the major obstacle/challenge in the biomedical research field? What is needed to overcome this obstacle/challenge?
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The investigation of neurological, psychiatric, behavioral, neurodevelopmental and pain disorders is massively handicapped by lack of capacity to study the disease process and genotype-phenotype relationships in the specifically affected neurons.
Animal models generally are neither true surrogates nor predictive for treatment of human disease. Furthermore, it is not currently possible to screen for new therapies targeted against disease phenotypes under physiological contexts with actual patient genotypes. Instead, targets are interrogated in heterologous expression systems, often without their natural network of accessory proteins. Furthermore many key aspects of human neurobiology cannot be modeled or screened; neuronal survival, axon growth, synapse formation and establishment of neural networks. In consequence, progress in developing novel treatments for developmental, neurodegenerative, behavioral, cognitive, motor and sensory disorders has been disappointing. Even in the limited cases of success, the resulting treatments often address symptoms without modifying disease progression.
Recently it has become possible to either differentiate embryonic and induced pluripotent stem cells into defined neural subtypes or to alternatively directly transdifferentiate readily accessible cell types such as fibroblasts to a particular neuronal identity. However, only a handful of defined neurons have been produced, and even fewer diseases phenotyped so far, and using this novel approach to screen for new therapies is just beginning, at a very small scale. |
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What emerging scientific opportunity is ripe for investment by the Common Fund?
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Exploiting stem cell and neurodevelopmental biology to define the transcription factor and miRNA code for every neuron in the nervous system and exploiting this, together with morphogens, to screen for the most efficient way of producing defined neuronal subtypes.
Recognition that human neurons made in this way offer an opportunity to study the fundamentals of human cellular and molecular neurobiology as well to capture key aspects of disease phenotype. |
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What are the potential Common Fund investments that could accelerate scientific progress in this field?
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- Identify the specific transcription factor code for the differentiation of individual neurons.
- A battery of tal-effector nucleases that will allow gene targeting at a diversity of transcription factor genes, disease related targets and other loci with important neural function.
- Identify suitable reporters for identification of neuronal subtypes.
- Produce a full universe of transcription factor vectors and other reagents and provide capacity to conduct unbiased screens of optimal transcription factor combinations to drive efficient and specific differentiation of neurons.
- Study how to differentiate neurons to a mature phenotype.
- Use these neurons to study excitability, axon growth, synapse formation, neuronal survival and neural networks,
- Provide capacity to screen for different disease phenotypes in neurons. |
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If a Common Fund program on this topic achieved its objectives, what would be the impact?
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Access to reagents, cells and protocols that would allow individual investigators and industry to make defined neurons from control subjects and patients and then use this to study cell and molecular biology of the nervous system, changes that occur in disease as a consequence of genetic mutations or polymorphisms, risk and susceptibility factors for disease progression, as well as screen for novel interventions, would collectively, be transformative. It would change the way human neuroscience research is conducted and how new therapies are identified and validated; in particular the capacity to study neural function in human neurons and screen for new therapies based on correcting disease phenotype in a diseased cell. This should also help enable identification of the optimal treatment for individual patients.
Apart from the obvious translational aspects, the project would generate import knowledge concerning the nature of developing and maturing neural sub-types. These transcription factor codes would be a neurodevelopmental "atlas" for the differentiation of neuronal subtypes, which would be invaluable |
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