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Non-canonical activation of heterotrimeric G protein signaling in vivo

异源三聚体 G 蛋白信号传导的体内非典型激活

基本信息

批准号：
10018921
负责人：
Mikel Garcia-Marcos
金额：
$ 43.73万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018921
关键词：
Affect Animal Model Apical Binding Biochemical Biological Assay Biological Process Biosensor Brain Case Study Cell physiology Cells Congenital Abnormality Congenital Hydrocephalus Cues Cytoplasmic Protein Data Development Disease Edema Embryo Embryonic Development Encephalopathies Eukaryota Family Family member G-Protein-Coupled Receptors G-substrate GTP-Binding Proteins Genetic Goals Guanine Nucleotide Dissociation Inhibitors Guanine Nucleotide Exchange Factors Guanosine Triphosphate Health Heterotrimeric GTP-Binding Proteins Hormones Human Hydrocephalus Hypsarrhythmia In Vitro Intercellular Junctions Knowledge Measures Mediating Mediator of activation protein Molecular Mutate Neurodevelopmental Disorder Neurotransmitters Optic Atrophy Optics Pharmacology Physiological Processes Physiology Proteins Regulation Research Role Signal Transduction Signaling Protein Specificity Subgroup Syndrome System Visualization base cancer cell constriction drug market genetic regulatory protein human disease in vitro activity in vivo infancy innovation insight intercellular communication interest nervous system development neurodevelopment novel optogenetics protein activation prototype receptor recruit synthetic construct technological innovation tool

项目摘要

ABSTRACT SIGNIFICANCE: Heterotrimeric G proteins are quintessential mediators of intercellular communication. Defining the molecular mechanisms by which this widespread machinery is regulated is of paramount importance because it impacts a vast range of physiological processes and diseases. This is well exemplified by the ongoing research interest in G protein-coupled receptors (GPCRs), the canonical activators of heterotrimeric G proteins and the targets for >30% of marketed drugs. A much less studied aspect of heterotrimeric G protein regulation, but with far-reaching implications, is their “non-canonical” activation by proteins that are not GPCRs. Among these non-GPCR activators, proteins containing an evolutionarily conserved Gα-Binding-and- Activating (GBA) motif, namely “GBA proteins”, have emerged a key new players in the control of G protein signaling in health and disease. GIV and DAPLE are the prototype members of this family of G protein regulators and both of them are mutated in neurodevelopmental disorders in humans that result in brain birth defects. DAPLE is mutated in non-syndromic congenital hydrocephalus (NSCH) whereas GIV is mutated in Progressive Encephalopathy with edema, Hypsarrhythmia, and Optic atrophy (PEHO)-like syndrome. The cellular and molecular alterations that cause these diseases are poorly understood. BACKGROUND AND GOALS: One of our long-term goals to date has been to identify and characterize a family of cytoplasmic proteins with a GBA motif that activates G protein signaling. Like GPCRs, they have Guanine-nucleotide Exchange Factor (GEF) activity in vitro. Within this context, our goal here is to understand mechanistically how this in vitro GEF activity relates to activation of G proteins and G protein-dependent signaling in living cells, and to establish the importance of this mechanism in vivo. SYNOPSIS OF AIMS: We will (1) dissect how GIV and DAPLE, the two prototype GBAs, affect G protein signaling in cells by using novel chemogenetic platforms and G protein activity biosensors, (2) define how their function is regulated by extrinsic cues by using cell biological assays and novel optogenetic tools, and (3) characterize their impact on neurodevelopment by using animal models. INNOVATION AND IMPACT: Overall, we anticipate that this project will advance the field of heterotrimeric G protein signaling by providing detailed mechanistic insights into a poorly understood aspect of their regulation that impacts human health, and by generating a suite of chemogenetic, optogenetic and biosensor tools to directly manipulate and detect heterotrimeric G protein activity with unprecedented accuracy. The conceptual and technological innovations arising from the successful completion of this project would have a long lasting impact in the field of signal transduction.

摘要