Congratulations Mike Grossheim, PhD
On Wednesday, July 8 2020 Jonathan 'Mike' Grossheim successfully defended his dissertation and earned his PhD. Congratulations, Dr. Grossheim!
REMODELING IN THE ACTIN CORE OF THE AUDITORY HAIR CELL STEREOCILIA AS A NOVEL COMPONENT OF TEMPORARY NOISE-INDUCED HEARING LOSS
Doctoral Committee Members
Dr. Gregory Frolenkov, Department of Physiology, Mentor
Dr. Paco Andrade, Department of Physiology
Dr. Tim McClintock, Department of Physiology
Dr. Karyn Esser, Department of Physiology (formerly)
Dr. Becky Dutch, Department of Molecular & Cellular Biochemistry
Dr. Elizabeth Debski, Department of Biology, Outside Examiner
Abstract
The rigid, paracrystalline actin core of auditory hair cell stereocilia is extremely stable and after initial formation must persist for the life of the cell to preserve hearing in mammals. In healthy hair cells, turnover of actin occurs only in a small region near the tips of stereocilia, while the actin filaments of the shaft are stable. For decades damage to the actin core of stereocilia from acoustic trauma has only been attributed to cases of permanent noise-induced hearing loss. Here, we show that repairable actin core damage occurs in temporary noise-induced hearing loss from moderate acoustic trauma. We have found damage to the actin core in the form of small, submicron breaks in the filamentous actin (F-actin) at the base of the stereocilia, and displacement of the stereocilia from its anchoring rootlet after moderate noise exposure causing a temporary shift in the auditory threshold. The same damages were recapitulated in vitro after mechanical overstimulation of stereocilia bundles by fluid-jet. Despite the well-established stable nature of the F-actin within stereocilia, we observed complete repair of this damage in vitro and partial repair in vivo. The mechanism of this repair remains unclear but appears to involve actin remodeling in the upper portion of the rootlet located within the stereocilia shaft. Our results suggest that repairable damage to the F-actin at the base of stereocilia is a novel component of temporary noise-induced hearing loss. We believe that restoration of hearing thresholds after moderate noise exposure includes the repair of this damage. Although the exact mechanism of this repair is unknown, this is the first evidence for actin cytoskeleton repair in the stereocilia of auditory hair cells which have to maintain their structure and mechanosensitivity throughout the life of an organism
Acknowledgements
This dissertation is the denouement of a 25-year-long odyssey in higher education. The path has been non-traditional, arduous, and protracted. Nevertheless, despite a myriad of hardships over the years, the direction has remained steadfastly and inexorably forward. Although there were times when the abdication of my pursuit seemed inevitable, the journey has come to its successful end and, true to its purpose, has culminated in a faculty position educating future healthcare providers and aspiring scientists. Nearly 400 years ago, as part of his Devotions upon Emergent Occasions, John Donne wrote, “No man is an island, entire of itself…” Notwithstanding the likelihood that Donne’s use of “man” was not intended as a sobriquet for “human,” and despite the vituperations such a philosophy receives today from those espousing bootstrap levitation as pragmatic, I embrace the sentiment from a humanist perspective. While not ignoring the relevance of such a credo to the crises of our time, I instead utilize it here in multipartite fashion to concede not only that this accomplishment is not mine alone, but also that my failure to fully attribute more than 4 decades of innumerable contributions from others is inescapable. I wish to thank my advisor and committee chair, Dr. Gregory Frolenkov, for his guidance and stalwart support over the years; these many, many years. From the very first day of my time in his lab I was forthright with my aspirations... I do not think he believed me. I have seen him inspire students in the lab to pursue careers in research and I think he believed he might be able to do the same with me. The exact moment at which he was fully disabused of this notion may never be known, but I do know that it improved our dynamic. Unfortunately, even with that realization we still do not speak the same language, and this led to many a strident misunderstanding as a result. Although we have not always seen eye to eye during the process, this dissertation would not have been possible without him. I have a great deal of respect for Gregory’s talents and I am delighted to leave the research to his capable hands. I want to thank the other members of my PhD committee: Dr. Francisco ‘Paco’ Andrade, Dr. Rebecca Dutch, Dr. Karyn Esser, and Dr. Timothy McClintock. Their advice, insight, and encouragement throughout the prolonged and unconventional path to my PhD is much appreciated. Along with Gregory, they have been my Sherpas as I sought the summit in an environment for which I am ill-suited. An extra thank you to Dr. Karyn Esser for remaining on the committee after relocating to the University of Florida. I would also like to thank Dr. Elizabeth Debski for consenting to serve as the outside examiner for my defense. Many people have come and gone from the Frolenkov lab during my tenure and they have all contributed in one way or another. I owe a huge thanks to Cata, Dr. Alejandra Catalina Vélez-Ortega, for invaluable assistance more times than I can count. Cata is a wonderful mentor and I am extremely excited for her future as she establishes her own lab and embarks on her career as a PI. I still cannot believe my good fortune to have been in the lab with Stephanie Edelmann. Stephanie and I always had fun as she shares my sense of humor, my passion for teaching, and my ability to find trouble. I often referred to Stephanie as a chocolate lab, because every new person she comes across is just a friend she has not met yet. There was a void in the lab when she left but it turned out that there was a yellow lab who would come and fill that void with an ebullient attitude as bright as the sun. Mary Freeman was that yellow lab and it was a marvelous boon to have had her warmth and positivity during some dark times. I also want to thank Dr. Desislava Marinkova for sharing some of her ABR data to bolster my own. To Abbey, Caro, Isabel, Shawn, Shadan and all the others in the lab, past and present, thank you! Of course, I would be remiss if I did not thank my family and friends: My parents and grandparents, whose influence while growing up cannot be overstated in shaping the way I look at the world. My mother Debbie, who provides love, support, and exasperation in near equal measure. My non-consanguineal family (both those I have ‘adopted’ and those who have ‘adopted’ me) who have been there through thick and thin. Especially my best friend Kristy, her husband, and their two amazing children, whose imprint on my life is indelible. Meine deutschen Freunden, die immer so liebevoll sein. Deutschland ist die Heimat meines Herzens und hoffentlich wird es eines Tages meine Heimat in Wahrheit sein. To include all of my friends would be a Herculean task. Instead I will express my gratitude that my friends know how much I value them without needing the validation of being mentioned in a document destined to be read by only 6 people. Having saved the best for last, I want to thank my wonderful husband, Tyler Robert Grossheim. The constancy of his love, companionship, wit, and humor has buoyed my spirits during difficult periods and been my bulwark against despair. Together with the unconditional love of our furry, four-legged compatriot Chewy, he has brought joy and contentment to my life. Hand in hand we confidently head into the future, invigorated, and excited to face the challenges ahead. Adventure awaits.
