Structure and function of L-type channels in lymnaea stagnalis

我的假设驱动研究计划的目标是检查l型钙通道的结构和功能。这些通道参与许多基本的大脑功能，例如：1)控制呼吸、进食和运动等节律性行为的模式神经活动；2)神经元的可塑性，这是我们如何学习和记忆的基础；3)神经元间突触连接的生长发育。对后者的研究对于能够利用受创伤的大脑或帕金森氏症等病变大脑的神经再生能力尤为重要。我们也在用来自有毒无脊椎动物的肽毒素筛选l型通道，以确定潜在的药物。迄今为止，针对这些通道的药物不是脑特异性的，但在治疗心脏和循环系统相关疾病（如高血压、心绞痛和心律失常）中广泛使用。鉴定出的蜗牛特异性阻滞剂可能被改造成一种致命的、抗蜗牛的生物农药，以防止难以治疗的蜗牛相关疾病的传播。例如，目前，由蜗牛宿主携带的血吸虫病影响家养动物种群，每年还造成20万人死亡和2亿人致残。除了筛选新化合物，我们还模拟了l型通道的孔隙结构。建模为我们提供了一个机会来识别赋予选择性和药物敏感性的孔的残留物。在我的实验室里，学员将接触到多学科的方法，包括离子通道生物物理学、分子生物学、蛋白质生物化学和动物行为基础的综合生理学。他们还将接触到各种电生理技术，包括在体外转染离子通道水平上的记录，培养中的神经元和突触，甚至在完整的大脑中识别神经回路。学员将获得宝贵的经验，这将为他们提供终身在基础和临床生命科学研究，制药行业，政府机构和学术界的机会。

The goal of my hypothesis-driven research program is to examine the structure and functions of L-type calcium channels.  These channels participate in many essential brain functions, such as: 1) patterned nerve activity controlling rhythmic behaviours such as respiration, feeding and locomotion; 2) the plasticity of neurons, which underlie processes such as how we learn and remember; and 3) the outgrowth and development of synaptic connections between neurons.  Research into the latter will be particularly critical for being able to harness the power of nerve regeneration in brains injured by trauma or in diseased brains like Parkinson's.  We are also screening L-type channels with peptide toxins from venomous invertebrates to identify potential pharmaceuticals.  To date, medicinal drugs targeted for these channels are not brain specific, but widespread in the treatment of heart and circulatory-related conditions such as high blood pressure, angina and arrhythmias.  Identified snail specific blockers may be engineered into a lethal, anti-snail bio-pesticide to prevent transmission of poorly-treatable, snail-related diseases.  At present, for example, schistosomiasis, carried by a snail host, affects domesticated animal populations and is also responsible for ~200 thousand deaths and cripples ~200 million people every year.  In addition to screening for new compounds, we are also modelling the pore structure of L-type channels.  Modelling provides us with an opportunity to identify residues of the pore which confer selectivity and drug sensitivity. Lab trainees will be exposed to multidisciplinary approaches in my laboratory bridging the fields of ion channel biophysics, molecular biology, protein biochemistry and integrative physiology underlying animal behaviour.  They will also be exposed to a variety of electrophysiological techniques including recording at the level of transfected ion channels in vitro, neurons and synapses in culture and even identified neural circuits in the intact brain.  Trainees will gain valuable experience which will provide them with lifelong opportunities in basic and clinical Life Science research, the pharmaceutical industry, governmental agencies and academia.