Kalirin-7's role in synaptic transmission, plasticity and learning and memory

描述（由申请人提供）：本研究计划的总体目标是更好地了解kalirin-7在兴奋性突触传递和可塑性中的作用，以及这种蛋白质功能的破坏如何参与复杂的神经精神疾病，如精神分裂症和阿尔茨海默病。这个K99/R 00独立之路奖的申请人布鲁斯海岭博士是加州大学旧金山分校罗杰·尼科尔博士的博士后研究员。Herring博士的长期职业目标是领导一个基础神经科学研究的独立研究实验室，作为学术研究机构的终身制主要研究员。Herring博士的长期研究目标是使用细胞，分子，电生理，成像，生物化学和遗传方法的组合来阐明控制突触传递，突触可塑性和引起神经精神疾病的细胞和突触水平机制。虽然精神分裂症的病因机制仍然很大程度上未知，药理学，遗传学和形态学数据的融合暗示了脊柱稳定性，兴奋性传递和突触可塑性的失调。Kalirin-7已被证明在脊髓和突触发生和维持中具有关键作用，受DISC 1调节，DISC 1是一种与精神分裂症密切相关的蛋白质，并且KALRN基因中的几种突变已被鉴定为这种疾病的可能遗传风险因素。此外，CaMKII对N-末端苏氨酸残基（T95）的磷酸化增强了Kalirin-7激活参与调节突触形态的小GTP酶的能力。CaMKII在长时程增强（LTP）的诱导中是关键的，长时程增强（LTP）被认为是突触可塑性的主要机制之一，并且通常被认为是学习和记忆的细胞基础。然而，CaMKII磷酸化的目标负责引起LTP尚未确定。鉴于kalirin-7在LTP中的潜在作用，加上这种蛋白质在树突棘维持和许多神经精神疾病中的意义，可能表明kalirin-7代表了学习、记忆和神经精神疾病的分子机制之间的关键点。使用创新的遗传方法的组合，允许内源性kalirin在单个神经元中被重组kalirin-7突变体取代，Herring博士提出了一个系统的研究，通过CaMKII对kalirin-7磷酸化在兴奋性突触形态，功能以及学习和记忆中的作用。通过结合他在分子和细胞生物学，药理学和突触电生理学方面的培训，Herring博士将继续进行成像和生物化学方法的额外培训，以解决以下具体目标：1）确定kalirin-7磷酸化在兴奋性突触，学习和记忆调节中的作用; 2）确定kalirin-7和Trio是否代表支持LTP的冗余通路; 3）鉴定涉及kalirin-7的功能相关的蛋白质-蛋白质相互作用。这项申请的成功完成将确定新的机制和新的蛋白质的基础和调节LTP，并将开辟新的前沿发展的疾病修饰治疗方法的精神分裂症和其他神经精神疾病。此外，K99/R 00奖提供的培训期将为Herring博士的独立职业生涯提供强大的工具箱，以研究突触传递，可塑性和疾病的分子机制。

DESCRIPTION (provided by applicant): The overall goal of this research program is to better understand the role of kalirin-7 in excitatory synaptic transmission and plasticity and how disruption of the function of this protein might be involved in complex neuropsychiatric disorders such as schizophrenia and Alzheimer's disease. The applicant for this K99/R00 Pathway to Independence Award, Dr. Bruce Herring, is a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Herring's long-term career goal is to lead an independent research laboratory in basic neuroscience research as a tenure-track principle investigator in an academic research institution. Dr. Herring's long-term research goal is to use a combination of cellular, molecular, electrophysiological, imaging, biochemical and genetic approaches to elucidate the cellular and synaptic level mechanisms that govern synaptic transmission, underlie synaptic plasticity and give rise to neuropsychiatric disease. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic, genetic and morphological data implicates a dysregulation of spine stability, excitatory transmission and synaptic plasticity in tis disease. Kalirin-7 has been shown to have a critical role in spino- and synaptogenesis and maintenance, is regulated by DISC1, a protein heavily implicated in schizophrenia, and several mutations in the KALRN gene have been identified as possible genetic risk factors for this disease. Furthermore, phosphorylation of an N-terminal threonine residue (T95) by CaMKII augments kalirin-7's ability to activate small GTPases that are involved in regulating synapse morphology. CaMKII is critical in the induction of long-term potentiation (LTP), a phenomenon thought to be one of the primary mechanisms underlying synaptic plasticity and generally regarded as the cellular basis of learning and memory. However, the targets of CaMKII phosphorylation responsible for giving rise to LTP have not been identified. Given kalirin-7's potential role in LTP, coupled with the implication of this protein in dendritic spine maintenance and a number of neuropsychiatric diseases, may indicate that kalirin-7 represents a key point of convergence between the molecular mechanisms underlying learning, memory and neuropsychiatric disorders. Using a combination of innovative genetic approaches allowing endogenous kalirin to be replaced with recombinant kalirin-7 mutants in individual neurons, Dr. Herring proposes a systematic investigation into the role of kalirin-7 phosphorylation by CaMKII in excitatory synaptic morphology, function and learning and memory. By combining his training in molecular and cellular biology, pharmacology and synaptic electrophysiology, Dr. Herring will pursue additional training in imaging and biochemical methods to address the following specific aims: 1) Determine the role kalirin-7 phosphorylation plays in the regulation of excitatory synapses, learning and memory; 2) Identify whether kalirin-7 and Trio represent redundant pathways supporting LTP; 3) Identify functionally relevant protein-protein interactions involving kalirin-7. Successful completion of this application will identify new mechanisms and new proteins underlying and modulating LTP and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders. Furthermore, the training period afforded by the K99/R00 Award will provide Dr. Herring with a powerful toolbox for his independent career investigating the molecular mechanisms underlying synaptic transmission, plasticity and disease.