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. ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CFS (01))
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Mitler, Merrill
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Southern Illinois University School of Medicine
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Toth, Linda A; Trammell, Rita A; Williams, Robert W (2014) Mapping complex traits using families of recombinant inbred strains: an overview and example of mapping susceptibility to Candida albicans induced illness phenotypes. Pathog Dis 71:234-48
Trammell, Rita A; Cox, Lisa; Pikora, Joshua et al. (2012) Evaluation of an extract of North American ginseng (Panax quinquefolius L.) in Candida albicans-infected complement-deficient mice. J Ethnopharmacol 139:414-21
Trammell, Rita A; Toth, Linda A (2011) Markers for predicting death as an outcome for mice used in infectious disease research. Comp Med 61:492-8
Turner, Jeremy; Hughes, Larry F; Toth, Linda A (2010) Sleep, activity, temperature and arousal responses of mice deficient for muscarinic receptor M2 or M4. Life Sci 86:158-69
Ding, Ming; Arnold, Jennifer; Turner, Jeremy et al. (2010) Lack of association of a spontaneous mutation of the Chrm2 gene with behavioral and physiologic phenotypic differences in inbred mice. Comp Med 60:272-81
Johnston, Nancy A; Bosgraaf, Christine; Cox, Lisa et al. (2007) Strategies for refinement of abdominal device implantation in mice: strain, carboxymethylcellulose, thermal support, and atipamezole. J Am Assoc Lab Anim Sci 46:46-53
Ding, Ming; Toth, Linda A (2006) mRNA expression in mouse hypothalamus and basal forebrain during influenza infection: a novel model for sleep regulation. Physiol Genomics 24:225-34
Toth, Linda A; Hughes, Larry F (2006) Sleep and temperature responses of inbred mice with Candida albicans-induced pyelonephritis. Comp Med 56:252-61
Toth, Linda A; Hughes, Larry F; Rehg, Jerold E (2005) Sleep during concanavalin-A-induced hepatitis and peritonitis in inbred mice. Sleep 28:571-82
Toth, Linda A; Hughes, Larry F (2004) Macrophage participation in influenza-induced sleep enhancement in C57BL/6J mice. Brain Behav Immun 18:375-89

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