Research Project: Yr. 2 IHSFC Voucher- A Novel Mouse Model of Immunodeficiency to
Evaluate the Impact of Environmental Toxicants on Mitochondrial Dysfunction.
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- Threadgill, David
- West, Andrew
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Overall Project Description and Goals
Mitochondrial metabolic reprogramming is critical for the differentiation and function of hematopoietic stem cells and immune cell progenitors, particularly macrophages and T-cells. Indeed, patients with immunodeficiencies (IDs) are increasingly recognized to exhibit perturbation of mitochondrial function. Likewise, patients with primary mitochondrial diseases (PMDs) exhibit aberrant immune and inflammatory responses. In addition to these primary genetic diseases, environmental exposures such as l-methyl-4phenyl-l, 2, 3, 6-tetra-hydropyridine (MPTP), and pesticides such as rotenone and paraquat (PQ2+) target mitochondrial functions, causing oxidative stress, de-regulated innate immune responses and inflammatory disease. However, the molecular mechanisms responsible for orchestrating immuno-metabolic switches in macrophages and T- cells, and the potential synergistic contribution of environmental toxicants to mitochondrial dysfunction in IDs, remain largely unknown. Moreover, the significance of environmental toxicant exposures as potential triggers of immunodeficiency in PMDs has not been systematically studied.
While Nuclear Factor ?B (NF-?B) signaling is critical for innate immune responses, a role for NF-?B in regulating metabolic reprogramming or mitochondrial function in innate immune cells has not yet been investigated in the context of IDs and PMDs. Preliminary data demonstrated that NF-?B-inducing kinase (NIK) is required for the characteristic metabolic switching that occurs during myeloid differentiation, macrophage M1 and M2 polarization, acquisition of immune effector function, and normal hematopoietic differentiation. Our overarching hypothesis is that mitochondrial metabolic dysregulation is a key underlying cause of NIK-mediated immunodeficiency. This pilot project seeks to develop a novel, genetically engineered, humanized mouse model of ID caused by NIK loss-of-function. Specifically, we proposed to use CRISPR/Cas9 synthetic gRNAs to generate a C57Bl6 knock-in transgenic mouse with a known NIKCys-306-Val*2 mutation that was recently identified in ID patients and to use these mice to investigate how environmental toxicants that target mitochondrial functions synergize with de-regulated innate immune responses to impact human health and susceptibility to infectious disease.
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