A Subependymal Giant Cell Astrocytoma (SEGA) Mouse Model
Abstract
This application seeks to generate, characterize, and treat a novel mouse model of tuberous sclerosis complex (TSC). The TSC model produces mice with a type of brain tumor called a subependymal giant cell astrocytoma (SEGA). The proposal will help generate a better understanding of how SEGAs form and when and how we can improve therapies. The proposal will help address two Tuberous Sclerosis Complex Research Program focus areas. First, this application will help us to gain a deeper knowledge of TSC signaling pathways and the cellular consequences of TSC deficiency. We will perform studies that will help us understand precisely how SEGAs form. Second, this proposal will test and facilitate therapeutics, biomarker, and clinical trials research. We will study a new class of third-generation mTORC1 inhibitors tethered to rapamycin and exemplified by RapaLink1. We will determine the extent that RapaLink1 permanently reduces SEGA size and frequency. We will simultaneously study a U.S. Food and Drug Administration-approved molecule called all-trans retinoic acid (ATRA). This molecule was chosen on the basis that TSC cells have problems becoming the cell types they normally should become. If ATRA is successful, we would predict a rapid turn-around time for clinical use. My previous work tested the theory that loss of TSC genes in a cell in the brain called a neural stem cell (NSC) is responsible for abnormal brain development. The findings from these papers notably laid the groundwork for important clinical studies that demonstrated that loss of two TSC genes or certain types of severe mutations that occur in NSCs cause abnormalities in the cortex called cortical tubers. After birth, NSCs only exist until about 18 months of age in localized areas of the brain. One of these areas is called the subependymal/subventricular zone. Unfortunately, this is the area of the brain in which SEGAs normally form. We and another group tested the hypothesis that loss of TSC1 (hamartin) from this postnatal pool causes SEGA formation. While there were certainly many issues that arose, the abnormalities resembled immature SEGAs called nodules. For several years, this finding has bothered me, in part because no other genes besides TSC1 and TSC2 are responsible for TSC. This may reflect the fact that TSC1 mutations are frequently dominant negative mutations that result in TSC1 (hamartin) preventing normal TSC2 function. Therefore, the simple removal of the TSC1 gene does not adequately recapitulate what happens in many cases of TSC. After starting my own laboratory, I decided to look deeper into the mTOR pathway and TSC. Serendipitously, I chose to delete TSC2 (tuberin) from the postnatal subependymal/subventricular zone NSCs. NSCs normally generate neurons and our intention was to look at neurons. However, to our surprise, the SVZ NSCs developed into SEGAs. Since TSC2 (tuberin) has distinct biochemical functions, is associated with more severe clinical symptoms, and is most frequently associated with SEGA formation, this finding is, in retrospect, not surprising. Here we propose to carefully and closely examine how SEGAs form in this model. We will examine the cell types and cellular processes that are altered. We will examine how the biochemical pathways are altered within SEGA cells. And finally, and perhaps most importantly, we will perform side-by-side comparisons of two newer classes of drugs to determine whether we can permanently kill TSC SEGA cells. Because neurons are also generated from NSCs, we will also examine neuron biochemical pathways, morphology, and function. RapaLink1 effects on TSC neurons are completely unexplored, and we will examine whether RapaLink1 may also restore neuron morphology and function. Taken together, we believe that these studies are perhaps a last preclinical step for eradicating SEGAs, and because many of the molecular mechanisms responsible for SEGA growth may also cause lym
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 29, 2021
- Source ID
- W81XWH2010447
Entities
People
- David Feliciano
Organizations
- Clemson University
- United States Army