Defining Molecular Mechanism for Targeting the Female-Specific TSC-LAM
Abstract
The proposed work centers on the following Focus Area: Eradicating tumors associated with tuberous sclerosis complex (TSC) and TSC-associated lymphangioleiomyomatosis (LAM), including a deeper mechanistic understanding of TSC signaling pathways. In our laboratory of Rare Lung Diseases at the University of Pennsylvania Perelman School of Medicine, we have a long-standing history of studying molecular mechanisms underlying TSC and LAM with the ultimate purpose of finding a cure. The work for which our lab received the most recognition is the discovery of the TSC2 function as a negative regulator of mTOR. Our lab was the first to establish human LAM cell cultures to perform preclinical testing and demonstrate rapamycin’s efficacy for inhibiting mTOR and negating LAM cell growth. Most patients with TSC ultimately develop pulmonary lymphangioleiomyomatosis (TSC-LAM). However, almost all reported symptomatic LAM cases are in women, while sex hormones and pregnancy exacerbate the progression of the disease. The exact underlying mechanisms of women’s selective susceptibility to symptomatic TSC-LAM are still unknown and represent a critical knowledge gap. We have developed an animal model of TSC-LAM, which reproduces many features of human disease, including a female-specific, age-dependent lung structure and function decline exacerbated by pregnancies. Using this model, we discovered a new molecular pathway that plays a crucial role in TSC-LAM phenotype development – Wnt/beta-catenin pathway. Based on our preliminary data, we hypothesize that this pathway, together with estrogen regulation and TSC2-dependent mTOR activation, contributes to the metastatic properties of TSC-LAM cells, resulting in lung remodeling and pulmonary function decline, characteristics of female-specific TSC-LAM. In this application, we propose using our novel animal model and human LAM cell lines isolated from LAM lungs to study and target female-specific mechanisms of TSC-LAM. We will define the exact molecular mechanism of female-specific regulation of the Wnt/beta-catenin pathway in TSC-LAM cells. Next, we will test the efficacy of the in vivo targeting of this pathway by the available small molecule therapeutics. Lastly, we will use a combination of cutting-edge genomic and computational biology approaches to identify a set of other new potential druggable targets contributing to female-specific pathological features of TSC-LAM cells. Overall, this approach will generate critical information about novel molecular targets, uniquely specific for the female and male manifestations of TSC-LAM, that will allow us and other research groups to test them in preclinical and clinical studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210503
Entities
People
- Kseniya Obraztsova
Organizations
- United States Army
- University of Pennsylvania