Thursday, April 3, 2025
4/3/2025
Macrophage/Microglia dysfunction in age-related auditory nerve degeneration - PROJECT SUMMARY Age-related hearing loss (ARHL) is a major public health concern, as the United States population continues to age. Although hearing devices are available, they do not address the root causes of ARHL which include auditory nerve (AN) degeneration, including demyelination. There is an urgent need for novel treatment approaches that prevent or slow age-related AN degeneration. Recently, studies show that AN demyelination contributes to hearing impairments, however the exact mechanism of demyelination in the aging auditory system remains unclear. Myelin maintenance and repair is a life-long process, but the efficiency of myelin repair declines with age. The pattern recognition receptor Dectin-1 (Clec7a) has been implicated in demyelination and neurodegeneration. Preliminary data show: 1) increased macrophages/microglia in regions of demyelination in the aged human AN, 2) evidence of microglial phagocytosis of myelin in the human AN, and 3) upregulation of Dectin-1 expressing macrophages/microglia in the aged mouse AN. These data suggest that Dectin-1 may contribute to age-related macrophage/microglia dysfunction, demyelination, and AN degeneration. Although macrophages/microglia in the auditory system are well-documented, their contributions to AN degeneration are unclear. Based on previous studies and preliminary data, I propose that aging increases Dectin-1 expressing macrophages/microglia, creating a proinflammatory immune cell population that exacerbates demyelination and AN degeneration. Aim 1 will test the hypothesis that Dectin-1 expressing macrophages/microglia are proinflammatory and associated with AN demyelination in aged mice and human donors. In this aim, I will define the age-dependent changes in Dectin-1 expressing macrophages/microglia in AN demyelination using a combination of quantitative immunohistochemistry, 3D high-resolution imaging, and single nucleus RNA- sequencing. This study will evaluate inflammatory infiltration of Dectin-1 expressing macrophages/microglia in demyelinated regions of the AN in young and old CBA/CaJ mice and validate findings in human tissue. Dectin-1 expressing macrophages/microglia are predicted to express more proinflammatory markers in aged ANs in regions of demyelination. Aim 2 will test the hypothesis that reducing Dectin-1 expression will prevent myelin degeneration of the AN by decreasing microglia activation and limiting inflammation, thus preserving AN function. This study will use a global Dectin-1 knock-out mouse model to directly evaluate the effect of Dectin-1 depletion on proinflammatory macrophage/microglia activation and AN degeneration. Mice will undergo threshold and suprathreshold auditory physiology (e.g. auditory nerve responses and measures of phase locking values (PLV) to assess AN function). Dectin-1 KO mice are predicted to show less age-related AN demyelination, stronger PLV, and reduced proinflammatory activation. These studies will advance our understanding of macrophages/microglia in AN pathology and potentially reveal a new biomarker of AN degeneration.
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