Use of Double-Humanized Mice to Study Diverse Manifestations of SLE
Abstract
In recent years, we and others have used mouse models to demonstrate that gut microbiota plays important roles in systemic lupus erythematosus (SLE). However, the functions of specific gut bacteria appear to be distinct depending on the mouse model of choice, indicating the need for a better preclinical model for SLE: one that closely resembles not only the disease but also the interactions between gut microbes and the human host. Therefore, in this Idea Award project, our goal is to establish a Double humanized SLE mouse model (the DhuSLE model), in which the mouse would both: (1) possess an autoimmune-prone human immune system and (2) harbor gut microbiota originating from SLE patients. We will transplant patient fecal microbiota into the best available mouse model of the human disease, huNSG-pristane, and ensure the absence of endogenous mouse microbiota via two different methods: antibiotics-mediated removal and the use of germ-free mice. More importantly, we will use this novel model to test the hypothesis that SLE patients exhibit different clinical signs due to differences in their gut microbiota. This is an entirely new concept that will direct future investigations into whether and how human gut microbiota affects human SLE pathogenesis. We have the experience, tools, and clinical samples in hand to test this hypothesis. The novel DhuSLE model will become the best preclinical model for testing new prophylactic and therapeutic agents and will enable clinically relevant mechanistic studies into human SLE pathogenesis. Upon completion, the proposed studies could also initiate a new research direction: mapping specific SLE manifestations to signatures in the gut microbiota. Our long-term goal is to use gut microbial biomarkers to predict disease manifestations for newly diagnosed SLE patients, which would provide the basis for personalized medicine and thus benefit drug selection and patient prognosis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310343
Entities
People
- Xin Luo
Organizations
- United States Army
- Virginia Tech