This is a Mentored Scientist Career Development Award application for Dr. Tina L. Sumpter, Research Instructor in the Department of Dermatology, School of Medicine, at the University of Pittsburgh. Dr. Sumpter's prior training focused on the underlying molecular mechanisms of tolerance induction to non-self-antigens in the allogeneic system. Following, her appointment in the Department of Dermatology, Dr. Sumpter studied the mechanisms of cutaneous inflammation, and the role of neuro-immune regulation of mast cell (MCs). She focused on initiation and maintenance of IgE-mediated MC activation relevant for anaphylaxis and atopic dermatitis (AD). This award will support additional training in facets of skin biology, immunology and MC function, and translational research and in management, leadership and grantsmanship. This training is necessary for Dr. Sumpter's transition to an independent investigator studying allergic inflammation in the skin. This application will further analyze the mechanisms of MC activation specifically in AD, a common, debilitating skin disease that represents a serious health problem. We will delineate the initiatio of pathogenic T cell responses and local tissue damage aggravated by IgE-Ag activated MCs. AD correlates with increased secretion of pro-inflammatory neuropeptides and we will analyze their role in the initiation and maintenance of disease. Specifically, we will analyze the molecula pathways following MC activation by substance P, (SP) and/or hemokinin-1 (HK-1), both agonists of the neurokinin-1 and -2 receptors (NK1R and NK2R, respectively) expressed in MC. Indeed, NK1R and NK2R affect MC function, and neuro-immune regulation via these receptors is central in the pathologic immune responses of AD. This proposal will test the hypothesis that interfering with neuro-immune MC activation will minimize the immune component of AD. Our hypothesis will be tested in three aims.
Aim 1 will analyze the role of intracellular pathways initiated by neuropeptides in mast cell activation.
Aim 2 delineates the function of the NK2R in mast cell function in vitro and in vivo.
Aim 3, using two in vivo AD models will delineate the role of NKR in the cellular and molecular cascades relevant for AD. Furthermore, it will assess the therapeutic potential of NK receptor manipulation in AD. The overarching objectives of this application are to provide additional training necessary for Dr. Sumpter to establish herself as an independent researcher in translational cutaneous biology and to provide rationale for the introduction of clinically approved NK receptor inhibitors to treat relapses in AD patients.
Atopic dermatitis (AD) is a frequent and invalidating cutaneous inflammatory disease, accounting for 10-20% of all visits to dermatologists and affecting up to 20% of children and 3% of adults. The socioeconomic impact of AD is estimated to cost 0.9-3.8 billion dollars per year. Furthermore, AD is a risk factor for other atopic disease like food allergy and asthma. Current immunotherapy for AD is based on broad immunosuppression or desensitization approaches, whereas physiologically oriented, specific manipulations are lacking. Activation of MC by IgE-Ag complexes is central for initiation, maintenance and relapses of AD. The intensity and duration of the inflammatory function of IgE activated MC are controlled by pro-inflammatory neuro-mediators. Our proposal will analyze molecular pathways of neuro-immune activation of MCs to present innovative, physiologically relevant immune interventions for therapy of AD.
|Guo, H; Lu, L; Wang, R et al. (2016) Impact of Human Mutant TGF?1/Fc Protein on Memory and Regulatory T Cell Homeostasis Following Lymphodepletion in Nonhuman Primates. Am J Transplant 16:2994-3006|
|Phong, Binh L; Avery, Lyndsay; Sumpter, Tina L et al. (2015) Tim-3 enhances Fc?RI-proximal signaling to modulate mast cell activation. J Exp Med 212:2289-304|