Defining of Neurodevelopmental Pathways Regulated by Neuregulin- DISC1 Interactio

描述（由申请人提供）：该申请涉及广泛的挑战领域（08）基因组学和特定的挑战主题，08- mh - 102精神分裂症相互作用组。精神分裂症被认为是一种复杂的神经发育障碍，有许多遗传因素导致其病理，可能以相互关联或趋同的方式。精神分裂症的两个最强易感基因是神经调节蛋白1 （NRG1）和DISC1。尽管它们在发育中的大脑中广泛表达，并被认为在神经发育过程中发挥重要作用，但尚不清楚这些分子是否在功能上相互关联，以及这种相互作用如何影响大脑皮层发育。我们假设，这些遗传因素之间的功能相互作用的改变以及由此导致的大脑皮层神经回路形成的改变可能导致神经发育障碍，如精神分裂症。了解发育中的大脑皮层中这些重要的SZ易感性遗传因子之间的功能相互作用，对于描述最终导致精神分裂症的病理生理过程至关重要。为此，我们将(1)确定NRG1对发育中的大脑皮层中DISC1表达的影响及其潜在的信号传导机制；(2)确定NRG1-DISC1相互作用在大脑皮层形成中的功能意义。这种对精神分裂症的强易感性遗传因素如何在皮质发育过程中相互作用的综合分析将有助于破译一些关键的神经发育途径，这些途径的破坏可能导致精神分裂症的发展。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-MH- 102 Schizophrenia Interactome. Schizophrenia is thought to be a complex neurodevelopmental disorder with many genetic factors contributing to its pathology, possibly in an interrelated or convergent manner. Two of the strongest susceptibility genes for Schizophrenia are neuregulin 1 (NRG1) and DISC1. Although they are broadly expressed in the developing brain and are thought to play important roles in neurodevelopmental processes, it remains unclear if these molecules are functionally related to each other and how this interaction affects cerebral cortical development. We hypothesize that changes in the functional interactions between these genetic factors and the resultant changes in the formation of neural circuitry in the cerebral cortex may lead to neurodevelopmental disorders such as schizophrenia. An understanding of the functional interactions between these important SZ susceptibility genetic factors in the developing cerebral cortex will be essential to delineate the pathophysiological processes that culminate in schizophrenia. To accomplish this, we will (1) determine the effects of NRG1 on DISC1 expression and the underlying signaling mechanisms in the developing cerebral cortex and (2) define the functional significance of NRG1-DISC1 interactions in the formation of cerebral cortex. This integrated analysis of how strong susceptibility genetic factors for schizophrenia interact during cortical development will help to decipher some of the key neurodevelopmental pathways whose disruption can lead to the development of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex neurodevelopmental disorder with many genetic factors contributing to its pathology in an interrelated or convergent manner. Two of the strongest susceptibility genes for Schizophrenia are neuregulin 1 (NRG1) and DISC1. Changes in the functional interactions between these genetic factors and the resultant changes in the formation of neural circuitry in the cerebral cortex may lead to schizophrenia. Therefore, we aim to define how susceptibility genetic factors for schizophrenia interact during cortical development. This will help to decipher the key neurodevelopmental pathways whose disruption can lead to the development of schizophrenia.