Research Interests
My current research interests include the following:
1. Understanding mechanisms of peripheral immunosuppression in GBM and other brain injuries
2. Determining the extent to which cell-free DNA affects T cells function
3. Determining serum-derived soluble mediators of immunosuppression in GBM
4. Defining the role of brain resident memory T cells in health and during neurological diseases
5. Investigating the role of immune organ innervation in health and during neurological injuries
6. Defining the role of antigen specific T cell generation and maintenance in primary immune organs
1. Understanding mechanisms of peripheral immunosuppression in GBM and other brain injuries
2. Determining the extent to which cell-free DNA affects T cells function
3. Determining serum-derived soluble mediators of immunosuppression in GBM
4. Defining the role of brain resident memory T cells in health and during neurological diseases
5. Investigating the role of immune organ innervation in health and during neurological injuries
6. Defining the role of antigen specific T cell generation and maintenance in primary immune organs
Selected Grants
Nervous system control and regulation of the immune system following neurological insults
ResearchPrincipal Investigator · Awarded by National Institute of Neurological Disorders and Stroke · 2023 - 2026Fellowships, Gifts, and Supported Research
Increased levels of cell-free DNA contribute to systemic immunosuppression by directly inhibiting T cell function in GBM ·
2023
- 2024
PI ·
Awarded by: Duke Spore CEP
· $50,000.00
This career enhancement program will allow our lab to mechanistically test the role of cell-free DNA in mediating T cell immunosuppression in glioma-bearing mice and to draw parallel in GBM patients.
Defining the role of cell free DNA in GBM induced immunosuppression ·
October 2022
- May 2023
PI ·
Awarded by: Brains together for a cure foundation
· $50,000.00
Glioblastoma is a deadly brain cancer with no cure. GBM also causes immune suppression. Immunosuppressive effects of GBM make this cancer hard to treat. Many therapies directed to use the immune system against GBM are reliant on the fact that the cells of the immune system outside of the brain are functional and have the capacity to get activated, proliferate, and kill the tumor. However, our research has previously shown that GBM patients and mice bearing gliomas do not have a functional immune system inside or outside of the brain. This likely makes any immunotherapies ineffective. It is then imperative to understand what causes immunosuppression and develop strategies to reverse this before attempting to deliver immunotherapies to GBM patients. We demonstrated that serum, which is the cell free portion of blood, isolated from glioma-bearing mice is extremely immunosuppressive and blocks functions of the immune system. We are studying what in serum of GBM-bearing mice and patients has the capacity to paralyze the immune system. We have so far narrowed down this immunosuppressive factor to a large molecule. Our recent data indicates that DNA levels are significantly increased in serum of glioma-bearing mice. There is also evidence that this DNA is in complexes that likely came from a neutrophil, a short-lived immune cell highly abundant in tumors and blood of GBM-bearing mice and humans. In this proposal, we will determine the source of DNA in serum of glioma-bearing mice and evaluate how DNA disables immune responses. We will also define whether serum-derived DNA originates from neutrophils and the extent depleting neutrophils improves outcomes. Having a cellular target allows us to develop strategies to remove DNA or the cell type releasing DNA from GBM patients with the hopes of rejuvenating the immune system and improving outcomes in GBM patients.
Nervous system control and regulation of the immune system following neurological insults ·
2021
- 2026
PI ·
Awarded by: National Institute of Neurological Disorders and Stroke
K99/R00 Pathway to independence award. Suppression of the immune system following damage to the central nervous system (CNS) is a common feature of neurological diseases as diverse as stroke, traumatic brain injury (TBI), and glioblastoma (GBM). This immunosuppression causes mortality and leads to the failure of immune-modulating therapies. The underlying mechanisms of systemic immunosuppression following neurological insults remain largely unknown. In this proposal, we focus on the thymus, the primary immune organ responsible for T cell development in children and adults. We tested thymic function following various neurological insults, including viral infections of the CNS, tumors, sterile inflammation, physical injury, and seizure activity. All insults resulted in significant thymic involution that was reversible upon clearance of the injury. Importantly, thymic involution did not occur following peripheral insults. Using parabiosis, we found that thymic involution was transferable from glioma- bearing to non-tumor-bearing parabionts demonstrating the crucial role of serum-derived soluble factors in mediating thymic involution. Specifically, serum-derived molecules with molecular weights (MW) larger than 300 kDa were deemed immunosuppressive. Interestingly, the thymus is heavily innervated by the CNS, yet the role of this innervation during neurological injuries and immunosuppression remains unknown. We demonstrated, for the first time, that the thymus is heavily innervated by both extrinsic neurons (cell bodies outside of the thymus), and intrinsic neurons (cell bodies within the thymus) using rabies virus neurotracers. In short, the multifaceted immunosuppression following neurological insults alters immune homeostasis in the thymus, bone marrow, and the spleen. The extents to which these alterations in the immune organs induce transient or long-lasting immunological defects remain understudied. Thymic involution, presence of immunosuppressive factors in serum, changes within the bone marrow niche, and long-lasting immunological defects together account, at least in part, for immune deficiencies observed following neurologic injuries. Based on these data, we hypothesized that following neurological insults the brain suppresses the immune system both systemically and locally through soluble factors and innervation. This in turn alters the immune repertoire and affects long-term immunity. This hypothesis will be tested in the following three aims: Aim1: To determine the molecular identity of serum-derived immunosuppressive factors during neurological insults; Aim 2: To determine the function of thymic innervation at baseline and during neurological insults; Aim 3: To determine transient and long-lasting functional consequences of immunosuppression on the immune system following neurological injuries. Successful completion of these aims will significantly impact understanding of immunosuppression and nervous control of the immune system during neurological injuries and will help us develop new therapeutics to combat immunosuppression in a large cohort of patients with acute and chronic neurological traumas.
The role of Serpina3n in mediating glioma induced immunosuppression ·
2019
- 2020
PI ·
Awarded by: Brains together for a cure foundation
· $50,000.00
Mayo Clinic Immuno-oncology Program ·
2019
- 2019
Co-PI with Dr. Johnson ·
Awarded by: Mayo Clinic
· $100,000.00
Neuro-oncology T32 training grant ·
2019
- 2021
trainee ·
Awarded by: Mayo Clinic T32
Department of Molecular Medicine small grant ·
2018
- 2018
Awarded by: Mayo Clinic
· $3,000.00
Center for Multiple Sclerosis and Autoimmune neurology post-doctoral fellowship ·
2017
- 2018
Awarded by: Mayo Clinic
· $25,000.00
American Heart Association pre-doctoral fellowship ·
2016
- 2016
Awarded by: American Heart Association