Invading perivascular macrophages and microglia cell play a pivotal role in the neuropathogenesis of Human Immunodeficiency Virus (HIV) associated neurological disorders. As with many neurodegenerative diseases, the activation of macrophages and microglia cells in the central nervous system (CNS) is thought to contribute heavily to neuronal damage. However, these cells are very dynamic with a wide range of functions including neuroprotection and repair. It is becoming increasingly clear that strategies to modulate specific phenotypes of these cells have substantial therapeutic potential. The proposed studies will expand on ongoing research exploring how neurotrophin signaling through the p75 and TrkA receptors may suppress the neurotoxic activity of these cells with the intent of developing a novel neurotrophin-based anti- inflammatory therapy. Since little is known about the expression and functions of neurotrophin receptors on macrophages, characterization of the expression of the receptors and basic functional changes associated with neurotrophin stimulation is needed. The proposed studies will characterize the signaling pathways that contribute to the observed down regulation of inflammatory activity by these receptors. The potential receptor interactions and pathways are complex and advanced training in state of the art microscopy, imaging techniques, signaling pathway analysis, and flow cytometry techniques will greatly facilitate this effort. This training s available locally and from external focused workshops. Coursework, symposia and focused scientific meetings are included in the training plan to supplement gaps in current knowledge. In addition to attending focused sessions, this will provide opportunities for the candidate to actively present findings of the proposed work, while engaging and interacting with investigators from other institutions. Together the training will provide an in depth understanding of the dynamics of macrophage signaling in the context of various challenges and will provide new techniques to effectively measure changes in key signaling events associated with p75 and TrkA activation. The training plan also includes a strong focus on career development to ensure that the candidate will be prepared to transition from a student to a more mature investigator and eventually an independent translational researcher. Career development seminars and training sessions through the Science, Training and Diversity office covers research ethics, how to manage the many hurdles faced as a translational researcher and being a woman of color in the sciences, while also solidifying basic skills necessary for long-term success such as scientific writing, grant proposal development and public speaking. Overall, the plan is structured to support the long term goal of becoming a well rounded, creative and thought provoking neuroscientist capable of directing a program of research focused on the development of new therapies for neurodegenerative disorders.
Even with the success of antiretroviral treatment, persistent reservoirs of HIV remain in the brain that activate monocytic immune cells causing inflammation and degeneration. In our lab, novel compounds that regulate neurotrophin signaling are currently under investigation that offer the potential to dramatically reduce the damage and restore nervous system function. The proposed studies will investigate how neurotrophin receptor activation might be used to eliminate the destructive phenotype of monocytic cells and facilitate the development of novel therapies that protect the HIV-infected nervous system.
|Williams, Kimberly S; Killebrew, Deirdre A; Clary, Gillian P et al. (2016) Opposing Effects of NGF and proNGF on HIV Induced Macrophage Activation. J Neuroimmune Pharmacol 11:98-120|
|Meeker, Rick B; Williams, Kimberly S (2015) The p75 neurotrophin receptor: at the crossroad of neural repair and death. Neural Regen Res 10:721-5|
|Williams, Kimberly S; Killebrew, Deirdre A; Clary, Gillian P et al. (2015) Differential regulation of macrophage phenotype by mature and pro-nerve growth factor. J Neuroimmunol 285:76-93|
|Meeker, Rick; Williams, Kimberly (2014) Dynamic nature of the p75 neurotrophin receptor in response to injury and disease. J Neuroimmune Pharmacol 9:615-28|
|Meeker, Rick B; Williams, Kimberly; Killebrew, Deirdre A et al. (2012) Cell trafficking through the choroid plexus. Cell Adh Migr 6:390-6|