The Role of CD3+ T Lymphocytes in Intervertebral Disc Repair and Aging - PROJECT SUMMARY The spinal column is an invaluable structure of the musculoskeletal system and the defining characteristic of vertebrate animals. An essential component of the spinal column is the intervertebral disc (IVD), a connective tissue that provides the shock absorption and weight distribution biomechanical properties of the spine. IVDs are complex, heterogeneous structures that are prone to cumulative damage over time due to a limited reparative capacity. The accrual of IVD injuries leads to IVD degeneration, which is associated with debilitating back pain and a reduction in quality of life. Successful repair of connective tissue injuries relies on temporally regulated immune cells that rapidly infiltrate damaged tissues and initiate tissue repair signaling cascades to restore homeostasis. CD3+ T lymphocytes are essential mediators of tissue repair and rapidly infiltrate musculoskeletal tissues to prevent further damage and stimulate repair after injury; however, the types of T lymphocytes that infiltrate during the acute IVD injury response, their effect on tissue repair, or how their functions are altered with aging remains understudied. Aging further impairs tissue repair and is a significant risk factor for experiencing IVD related pain since 80% of people over the age of 50 will exhibit IVD degeneration. Therefore, the objective of this study is to define the role of CD3+ T lymphocytes in the IVD acute injury response to identify targetable cell types to increase repair and prevent degeneration. The overarching hypothesis is that CD3+ T cells are essential for IVD repair after damage in young and aged mice and humans. The hypothesis will be tested with the following aims: aim 1) to determine the role of CD3+ T cells in tissue repair and function in young mice and human IVDs and aim 2) to determine the role of CD3+ T cells in tissue repair and function in aged mice and human IVDs. I will utilize methodologies like quantitative polymerase chain reaction, bulk and single cell RNA sequencing, histology, adoptive transfer, transgenic mouse models, flow cytometry, in vivo microscopy, and biomechanical testing in both rodents and patient IVD samples to address these aims. The proposed studies will identify novel roles for CD3+ T cells in the etiology of IVD pathology and repair and better inform pharma- therapeutic approaches to treat degeneration by increasing the reparative capacity of the IVD. I have an advisory committee of experts in musculoskeletal research, IVD aging pathobiology, immunobiology, γδ T cells, translational research designs, and mechanical testing, including my mentors Drs. Simon Tang and Lori Setton, who will provide invaluable training and guidance to accomplish these studies. In addition to my advisory committee, I will utilize seminars, courses, and meetings both at Washington University and through professional societies, such as the Orthopaedic Research Society, to provide further technical training, presentation experience, responsible conduct in research training, and the necessary skills to transition to independence.
