Sleep and fatigue during renal disease in mice

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DESCRIPTION (provided by applicant): Sleepiness and sleep quality broadly influence measures of general health status, particularly impacting perceptions about energy, fatigue, and general well being. Fatigue and disturbed sleep are also common and disabling problems for persons undergoing chronic diseases or associated therapies. In particular, people with renal disease frequently develop disturbed sleep and severe fatigue that can occur independent of dialysis. Intriguing data support significant interactions between sleep, immune function, and infectious or inflammatory disease, but the cause of fatigue and disturbed sleep during such disorders is uncertain. Identifying substances and mechanisms that modulate sleep and vigilance during disease states should contribute to the eventual development of interventions that can control or prevent these debilitating symptoms and thus improve the quality of life of many people. Our preliminary data indicate that inbred mice undergoing acute pyelonephritis induced by Candida albicans develop strain-dependent variation in patterns of sleep, and varying severity of disease. Our working model is that variation in the host defense response is linked to the development of symptoms such as fatigue and disturbed sleep, and to disease susceptibility and severity. Our long-term goal is to define this complex pathophysiologic network. Toward that end, we propose a genome-wide search to identify a still unknown set of genes that contribute to variation in the behavioral and/or physiologic responses to infection-induced renal disease. These studies will provide critical data necessary to definitively identify the genes that mediate alterations in sleep and to link those genes to other markers of illness. Aim 1 will assess murine strain differences in sleep during toxic nephropathy. Aims 2 and 3 will scan the genome to locate regulatory "hot spots." Aim 4 will capitalize on those findings by assessing the contribution of strong candidate genes. Achieving this ambitious goal is feasible given the experience of my laboratory in surveying sleep phenotypes in other studies involving large numbers of mice.