Schizophrenia (SZ) is a debilitating disorder with onset in young adulthood, with profound impact on the individual and society. Since 2008, we have made multidisciplinary efforts for this important medical question under the P20 and P50 support mechanisms. Based on our published works, promising preliminary results, and refined experimental strategies, we now conceptualize a new collaborative, hypothesis-driven research strategy towards a mechanistic understanding of SZ and related conditions. Through our past studies, we have obtained outcomes in five major areas: (i) microtubule-associated pathway as a developmental driver for the pathophysiology of SZ after puberty; (ii) changes in stress-associated molecules in SZ patients, particularly in early stages of the disease; (iii) aberrant cortical maturation in adolescence: potential gene-environment interactions during a critical period; (iv) neurocircuitry-guided behavioral characterization of mouse models associated with SZ; and (v) technological development in the analysis of RNA-sequencing data. Based on our own preliminary data as well as information published by other groups, we plan to address the following hypotheses in the coming five years: (a) genetic risks for SZ (or subset of SZ) elicit mild deficits during early brain development; (b) such deficits precipitate more prominent molecular and circuitry-related alterations later during adolescence; (c) stress-associated molecules activated during adolescence drive asymptomatic, vulnerable brains to a symptomatic, pathological state, directly affecting excitatory-inhibitory (E-I) imbalance; (d) such transitions are further exacerbated by psychosocial stressors in adolescence; and (e) intervention in the stress-associated transition is a key treatment strategy for SZ. To validate these hypotheses, we propose the following three Aims: (1) to define the contribution of genes encoding microtubule-associated proteins (microtubule genes) to SZ pathophysiology, in particular for a subset of SZ in which neurodevelopmental implications may be stronger; (2) to define how genetic risks in microtubule genes in early development precipitate changes in the prefrontal cortex (PFC) after puberty and how adolescent social stress may exacerbate such changes; and (3) to study how stress-associated molecules directly affect and impair the neural substrates that lead to E-I imbalance in adolescence, resulting in cognitive dysfunction in young adulthood, and how stressors during adolescence exacerbate these changes. To address these questions, we propose 3 projects and 3 cores that are fully integrated. We hope that our findings will inform molecular targets and appropriate timing for early detection and intervention for SZ, possibly for a treatment-resistant subset. Furthermore, by studying the circuitry and behavioral mechanisms underlying specific cognitive dimensions in SZ, we hope to contribute towards studies and treatment of adult-onset disorders with neurodevelopmental origins beyond SZ.
Schizophrenia (SZ) is a debilitating disorder with onset in young adulthood, with profound impact on the individual and society. Since 2008, we have made multidisciplinary efforts for this important medical question. Based on our published works, promising preliminary results, and refined experimental strategies, we now conceptualize a new collaborative, hypothesis-driven research strategy towards a mechanistic understanding of SZ and related conditions. We will focus on aberrant maturation of prefrontal cortex during adolescence by combining unique human tissue/RNA-sequencing data resources with mouse studies. Through the proposed study, we hope to make meaningful discoveries that will inform molecular targets and appropriate timing for early detection and intervention for SZ. In particular, we hope to address a specific, treatment-resistant subset of SZ with prominent negative and cognitive symptoms, in which neurodevelopmental implications may be stronger. Finally, by studying the circuitry and behavioral mechanisms underlying specific cognitive dimensions in SZ, we hope to contribute towards studies and treatment of young adult-onset mental disorders with neurodevelopmental origins beyond SZ.
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