Dimes Letter Of Intent Paper
March of Dimes Letter of Intent
1. Title of Proposal: Targeting β-catenin signaling in inhibitory circuitry for neurodevelopmental disorders
2. Hypothesis
Genetic factors play an important role in the etiology of neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorders (ASDs) that affect 3-4% of population worldwide. Intriguingly, highly penetrant mutations in β-catenin (β-cat) are frequently identified in patients with intellectual disability (ID) (1-6) and autism (7). Moreover, de novo mutations are enriched in genes regulating the Wnt/ β-cat pathway, suggesting that the β-cat signaling pathway represents a convergence of the genetic risks in neurodevelopmental disorder(8). The precise causes of these disorders are largely unknown. However, emerging evidence support that disruption of gamma-aminobutyric acid (GABA)ergic interneurons, particularly parvalbumin (PV)-positive neurons, contributes to pathological changes underlying in ASDs (9). To investigate the genetic risk in specific neuronal, our recent study demonstrated that β-cat knockout (KO) in PV interneurons causes many behavioral deficits similar to autism patients (10). Thus, our overarching hypothesis is that β-cat …show more content…
One of the major obstacles to identifying therapeutic interventions has been the difficulty of studying the step-by-step development of the underlying pathophysiology in systems amenable to drug screening. Using induced pluripotent stem cell models, our collaborator performed a pilot screen of ~1500 compounds from a library of FDA-approved drugs and known bioactive compounds(15). We have identified several bioactive compounds with diverse mechanisms of action that can potentiate the Wnt pathway, including approved drugs and probes suitable for in vivo use. We identified novel small molecules that modulate epigenetics and increase Wnt reporter activity (Fig.
1. Title of Proposal: Targeting β-catenin signaling in inhibitory circuitry for neurodevelopmental disorders
2. Hypothesis
Genetic factors play an important role in the etiology of neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorders (ASDs) that affect 3-4% of population worldwide. Intriguingly, highly penetrant mutations in β-catenin (β-cat) are frequently identified in patients with intellectual disability (ID) (1-6) and autism (7). Moreover, de novo mutations are enriched in genes regulating the Wnt/ β-cat pathway, suggesting that the β-cat signaling pathway represents a convergence of the genetic risks in neurodevelopmental disorder(8). The precise causes of these disorders are largely unknown. However, emerging evidence support that disruption of gamma-aminobutyric acid (GABA)ergic interneurons, particularly parvalbumin (PV)-positive neurons, contributes to pathological changes underlying in ASDs (9). To investigate the genetic risk in specific neuronal, our recent study demonstrated that β-cat knockout (KO) in PV interneurons causes many behavioral deficits similar to autism patients (10). Thus, our overarching hypothesis is that β-cat …show more content…
One of the major obstacles to identifying therapeutic interventions has been the difficulty of studying the step-by-step development of the underlying pathophysiology in systems amenable to drug screening. Using induced pluripotent stem cell models, our collaborator performed a pilot screen of ~1500 compounds from a library of FDA-approved drugs and known bioactive compounds(15). We have identified several bioactive compounds with diverse mechanisms of action that can potentiate the Wnt pathway, including approved drugs and probes suitable for in vivo use. We identified novel small molecules that modulate epigenetics and increase Wnt reporter activity (Fig.