Timothy Karr, Ph.D.

Associate Research Professor, Center for Mechanisms of Evolution, Biodesign Institute, Arizona State University

美国亚利桑那州立大学生物设计研究院副教授，翻译基因组学研究所（TGen）礼任教授。1981年获得了加州大学博士学位，博士后研究工作期间开始了对受精和早期果蝇形成的研究。2002年获得了英国皇家沃尔夫森研究优异奖。2006年和2010年，首次发表了对果蝇和小鼠精子蛋白组的功能基因组和进化的分析。2008年，成为亚利桑那州立大学生物设计研究院副教授。通过研究沃尔巴克氏体来识别并开发CI的分子机制，以制定出合理的害虫种群控制策略，开创了对果蝇沃尔巴克氏体生物学的研究。

Discovery proteomics and bioinformatics as a conduit for deeper insights into animal reproduction

A goal of systems biology is to integrate transcriptomic and proteomic data into models capable of bridging the “genotype-to-phenotype” chasm. A daunting, but necessary task, models that better interpret the burgeoning accumulation of sequence-based genetic variation among both human individuals and populations are needed for the development of new platforms for the detection and treatment of disease. A model system well suited for this task is the spermatozoa, a central player in the reproductive success of sexually reproducing organisms. Both humanfertility and infertility pose significant global health problems. In developing countries human fertility is the biological engine that drives population explosions thus producing associated societal and public policy issues impacting the human condition. Likewise, human infertility negatively impacts both individuals who desire children, and globally, where some countries are struggling with population-wide reductions in birthrates as often reported in the popular press and the subject of intense study by demographers, statisticians and sociologists. This is a significant problem because one-third of human infertility can be traced to a male factor of which some involve alterations in sperm proteins. Hundreds of genes are known to influence fertility in the mouse, but only a limited subset have characterized effects on sperm morphology or function. Although it is known in mammals, including humans, that Y chromosome deletions result in severe oligozoospermia or azoospermia, beyond this, the molecular understanding of other genes or genetic variants that result in male infertility or more subtle impairments in sperm viability, motility and metabolism remains limited. Sperm are remodeled and transformed into fully fertile, competent cells within the unique microenvironment created in the luminal duct of the epididymis, and there has been considerable interest in how epididymal proteins affect sperm function. The overall dynamics of maturation is poorly understood, and our research is engaged in a systems level analysis of this complex maturation process to provide valuable new information about changes occurring during epididymal transport. To begin, we have identified the proteomes of sperm collected from the caput, corpus and cauda segments of the mouse epididymis, identifying 1536, 1720 and 1234 proteins respectively, of which 765 proteins were common to all three segments (termed the “core” sperm proteome). Remarkably, we found that a total of 1766 proteins were either added to, (732) or removed from, (1034) sperm during epididymal transit. GO analyses revealed that cauda sperm are enriched for specific functions including sperm-egg recognition and motility, consistent with the observation that sperm acquire motility and fertilization competency during transit through the epididymis. In addition, GO analyses revealed that the immunity protein profile of sperm changes during sperm maturation. Finally, we identified components of the 26S proteasome, the immunoproteasome, and a proteasome activator in mature sperm.