Zinc is an essential nutrient required in over 300 known enzymes by organisms from all domains of life. Zinc deficiency in humans can result in low birth weight, impaired immune function, cardiac dysfunction and acrodermatitus enteropathica. Excess zinc can interrupt other non-zinc metalloproteins and can induce oxidative damage in cells such as neurons, which potentially leads to Alzheimer's Disease. Thus, cells must precisely regulate zinc homeostasis to ensure that they have enough zinc to allow proteins to function while minimizing the amount of excess zinc that can cause damage. The eukaryotic alga Chlamydomonas reinhardtii provides a perfect model system to study the regulation of zinc homeostasis because it can survive under a wide range of zinc-concentrations and contains putative zinc-responsive genes that are conserved in both animals and plants. To understand how Chlamydomonas senses and responds to zinc deficiency or toxicity, I propose the following specific aims: 1) To identify genes that are responsive to distinct stages of zinc nutrition and distinguish the operation of transcriptional vs. post-transcriptional mechanisms, 2) to identify zinc-responsive elements (ZREs) associated with one or more key zinc-responsive targets and assess the role of Crr1, a transcription factor known to regulate both zinc- and copper-responsive genes, in zinc homeostasis and 3) to use a classical genetic approach to identify components of nutritional zinc signal transduction, potentially including regulators and target genes. Studies of Chlamydomonas have already provided valuable insight into the mechanisms of iron and copper homeostasis, and details of zinc-homeostasis regulation will contribute to our broader understanding of how, cells evolved to take advantage of metal cofactors to perform the vital functions of life. Public Health Relevance: Zinc is an essential nutrient required in abundance by organisms ranging from bacteria to humans. Zinc is required by over 300 known enzymes, including those involved in respiration, transcription and photosynthesis. In this work, mechanisms of zinc-sensing and adaptive response will be unraveled to understand how cells recognize and adjust to zinc deficiency and toxicity.