约瑟夫·高桥

约瑟夫·高桥（Joseph S. Takahashi，），日裔美国遗传学家和神经生物学家，教授和霍华德·休斯医学研究所研究人员。高桥的课题组于1994年发现了哺乳动物生物钟的遗传学基础，在1997年确定出。高桥于2003年当选为美国科学院院士。
生平.
高桥1970年升入斯沃斯莫尔学院，1974年获得生物学学士学位。随后，他进入 南卡罗来纳大学以时间生物学研究见长的的课题组工作了一年，然后向德克萨斯州大学奥斯汀分校的申请工作机会，梅纳克也是时间生物学领域的专家。梅纳克转赴俄勒冈大学任教，高桥随之，并于1981年获得神经科学博士学位。获得博士学位后，高桥在做了两年博士后，随后在 西北大学神经科学和生理学系获得教职，后来，他在这里获得永久职位，并工作了26年 。2008年，高桥加入，任桑兹神经科学杰出讲席教授（Loyd B. Sands Distinguished Chair in Neuroscience），同时任Hypnion公司科学顾问，这家公司主要业务是开发影响睡眠、睡醒和生物钟紊乱的中枢神经系统疾病的创新疗法。高桥还是《神经元》、《生理基因组学》、《生物节律学报》等著名学术期刊的编委。
学术研究.
生理起搏器视交叉上核（SCN）的研究.
1980年代初，高桥和梅纳克以试管内鸟松果体为研究对象，以研究昼夜节律振荡，他们证明哺乳动物的昼夜节律控制中心下丘脑的视交叉上核（SCN），在鸟类动物中有相同的作用。他们与德库西合作，以仓鼠做实验，证明了负责调控昼夜节律的感光系统与视觉系统不同。
2010年，高桥与人合作，研究了调控生物振荡的温度涨落的潜在作用。他们发现，主生理起搏器通常只受环境明暗循环调控，但分离在试管后，还能受到温度涨落的调控，这表明温度复位是所有哺乳动物的生物钟的重要性质，很可能在哺乳动物所有细胞中，通过一个非常保守的机制起作用，这也说明，全身组织的体温节律是主生物钟与昼夜节律同步的一个可能机制。
哺乳动物生物钟基因的节律性质研究.
高桥的研究给促进人对哺乳动物生物钟对生理学与环境关系的研究。1993年，高桥与合作，研究了哺乳动物视交叉上核受环境光循环交叉的调控，研究了和"c-fos"蛋白转录之间的关系。借助免疫沉淀法，高桥和格林伯格证明了光致CREB磷酸化作用只在夜晚发生。-->
松果体体外研究有着明显的局限性，高桥利用和定位克隆技术研究昼夜节律的遗传和分子基础。1994年，高桥及其同事分离出了，1997年，他们克隆出了哺乳动物的CLOCK基因。
2000年，高桥克隆出了1988年就被发现的"tau"基因，他称此为自己最重大的科学成就之一。高桥发现，该基因与果蝇"dbt"基因和人类"CKIe"基因密切相关。
In 2000, he and his colleagues at Northwestern recognized that "clock" mutant mice slept 1 to 2 hours less per night than wild type mice. Additionally, because these mice lack the circadian system that regulates consolidated sleep at a certain time of day, sleep in "clock" mutants is spread out throughout the day in both light-dark cycles and in complete darkness. This mutation results in less REM sleep and more time spent in earlier sleep phases.
In 2005, he collaborated with Joseph Bass and reported the effects of mutations in the "clock" gene on the metabolism and physiology of mice. Their experiments compared weight gain in "Clock" mutant mice to that of control mice and showed that mutant mice were more likely to gain weight. Such a discovery influenced them to pursue exploration of the "clock" gene's role in appetite and energy. In "Clock" mutant mice, they reported depressed levels of orexin, a neuropeptide involved in regulation of eating. This result provides further evidence that the "clock" gene has a profound impact on metabolic processes in mice.
It has since been discovered that metabolism itself plays a role in regulating the clock. In 2009, Takahashi and his colleagues discovered that nicotinamide phosphoribosyltransferase (NAMPT) mediated synthesis of metabolic coenzyme nicotinamide adenine dinucleotide (NAD+), which both oscillate on a daily cycle, may play an important role in regulating circadian activity. By measuring the oscillations of NAMPT and NAD+ levels in the livers of both wild-type and mutant mice they determined that oscillations in NAMPT regulated NAD+ which in turn regulated the deacetylase SIRT1.
Continued mutagenesis studies.
Using mutagenesis screens (forward genetics) found both the "clock" mutant mouse and the tau mutant hamster. Takahashi's lab has continued use of this method in order to lead to discoveries of the role of the circadian clock in vision, learning, memory, stress, and addiction, among other behavioral properties.
In 2007, Takahashi and his colleagues at Northwestern ran a forward mutagenesis screen in mice looking for variations in circadian oscillations and subsequently identified a mutant which they named "overtime" ("Ovtm"). Using positional cloning, genetic complementation, and in-situ hybridization Takahashi and colleagues discovered that "Ovtm" was a point mutation that caused a loss of function in FBXL3 – an F-box protein – and was expressed throughout the brain and in the SCN. Assaying expression of known circadian clock genes in the "Ovtm" mutants, they observed a marked decrease in PER1 and PER2 protein and mRNA levels in the brain and a significant decrease in "cry2" mRNA levels only. Takahashi and his colleagues proposed that FBXL3 is a target site for protein degradation on the CRY2 protein, which would explain relatively normal CRY2 protein levels. Negative feedback by other elements of the circadian clock could then lead to the roughly 26 hour free-running period observed in "Ovtm" mice.