Systems Genetics of Tuberous Sclerosis Complex Outcomes Using BXD Recombinant Inbred Mice
Abstract
The goal of this project is to improve mouse models of tuberous sclerosis complex (TSC) in order to identify genetic factors conferring resilience to neurological symptoms. TSC is a profoundly complex disease characterized by cortical tubers and accompanied by epilepsy and TSC-associated neurological disorders (TANDs), including intellectual disability, developmental delay, anxiety, and autism spectrum disorder (ASD). Although TSC has been traced to gene mutations in the human TSC1 and TSC2 genes, patients with TSC-causing mutations have widely varying outcomes, ranging from intractable epilepsy and autism to no seizures or psychiatric comorbidities. Even within families sharing an identical TSC mutation, case reports indicate that some members can be clinically unaffected, while others are developmentally delayed and suffer from treatment-resistant epilepsy. Thus, there must be other genetic factors beyond the TSC gene mutation that determine outcomes. Identifying genetic factors conferring either resilience or susceptibility to adverse outcomes is a potentially powerful way to identify new possibilities for therapy. Mouse models are ideal for this work because they can be genetically controlled and extensively characterized biologically. In this project, we will develop a novel family of mouse models called the BXD-TSC mice to model patient heterogeneity and identify new genetic factors determining resilience or susceptibility to adverse outcomes. The objective of this project is to: (1) breed mice carrying a TSC-causing mutation to a diverse panel of mice called the BXD lines; (2) characterize their behavior, seizures, and brain abnormalities; and (3) genetically map these traits to identify resilience and susceptibility factors. The rationale for this study is that behavior, seizures, and brain abnormalities are intricately linked to each other and determine the complex neurological and psychiatric outcomes in patients with TSC. Because these outcomes are major determinants of quality of life, improved modeling of patient heterogeneity––and the subsequent effect on therapeutic development––is expected to benefit this group specifically. Such efforts are critical, as neurological and psychiatric outcomes are poorly controlled and even more poorly understood. Developing and validating a model system for patient heterogeneity is an investment to improve our ability to probe the basic biology of TSC and robustly preclinically test potential therapies. Improved TSC mouse models are expected to have a long-term translational impact on TSC research over the next 5 to 10 years. In the interim, this project will establish that genetic modifiers of TSC outcomes exist in the BXD-TSC mice, leading to near-term efforts to pinpoint these factors and determine their mechanisms. Beyond genetic research, this project will also provide the TSC research community with a new set of easily generated models to study the diversity of outcomes (including non-neurological outcomes). Moreover, this project will establish a novel experimental paradigm for identifying genetic modifiers of other TSC mutations, beyond the specific mutation in this project. The near-term adoption of this paradigm will therefore provide a platform to radically expand our ability to probe the pathophysiology of TSC leading to long-term improvements in patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910251
Entities
People
- John Mahoney
Organizations
- United States Army
- University of Vermont