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mTOR signaling in lung homeostasis, aging and disease

mTOR 信号在肺稳态、衰老和疾病中的作用

基本信息

批准号：
10394731
负责人：
VERA P KRYMSKAYA
金额：
$ 48.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394731
关键词：
Acceleration Address Adjuvant Affect Age Aging Alleles Alveolar Antiestrogen Therapy Applications Grants Biomedical Research Cells Characteristics Clinic Cyst Data Diagnosis Disease Disease Progression Epithelial Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogens FDA approved FGF7 gene FRAP1 gene Female Future Genetic Genetic Transcription Gonadal Steroid Hormones Homeostasis Human Human Characteristics Lesion Lung Lung Lymphangioleiomyomatosis Lung diseases Lymphangioleiomyomatosis Mesenchymal Mesenchymal Stem Cells Mesenchyme Microscopic Mission Modeling Mus Mutation National Heart, Lung, and Blood Institute Pathogenesis Patients Pharmaceutical Preparations Play Predisposition Pregnancy Proteins Risk Risk Factors Role SDZ RAD Signal Transduction Sirolimus Smooth Muscle Structure TSC1/2 gene TSC2 gene Tamoxifen Testing Therapeutic Tuberous Sclerosis Up-Regulation Woman Women&apos s Health age related alpha Actin functional decline gain of function improved in vivo insight lung lesion male mouse model novel novel therapeutic intervention overexpression pre-clinical pulmonary function pulmonary function decline sex side effect

项目摘要

Abstract Uncontrolled activation of the mechanistic target of rapamycin (mTOR) is a cause of pulmonary lymphangioleiomyomatosis (LAM), a predominantly female, rare genetic lung disease triggered by bi-allelic inactivating mutations in the mTOR’s upstream negative regulator the tuberous sclerosis complex (TSC1/TSC2) genes. The loss of TSC2 function and mTOR activation are associated with formation of microscopic smooth muscle-like LAM lesions and lung cysts - leading to spontaneous pneumothoraxes and progressive loss of pulmonary function primarily in women. Our lab pioneered the idea of using mTOR inhibitory drugs for LAM. Unfortunately, targeting mTOR with FDA-approved drugs Sirolimus or Everolimus (rapamycin) only delays the disease progression while causing lasting side effects in up to 60% of women. In addition, even with current treatment, some LAM patients are unresponsive to the rapalogs. Thus, despite significant progress, key unanswered questions remain, including: 1) how do only ~5% of the lung cells, which are bonafide “LAM cells” carrying genetic TSC2 mutations and mTOR activation, promote cystic remodeling of the whole lung? 2) what is the role of estrogen in making LAM a predominantly female disease? and 3) why is the risk of LAM is age- dependent? The objective of this proposal is to test our overarching hypothesis that mTOR activation in LAM cells deregulates their secretome and alters lung mesenchymal-epithelial crosstalk. We will explore whether sex predilection and pregnancies exacerbate these changes accelerating lung function decline in females. Our translational hypothesis states that anti-estrogen therapy represents a potential opportunity for fast tracking this hypothesis to benefit predominantly female LAM patients. The proposed study will yield essential new insights into the role of TSC2-dependent mTOR activation and estrogen on age-dependent lung structure and function with specific focus on a rare, predominantly female lung disease LAM. We will also perform preclinical anti- estrogen studies to explore future prospects for novel adjuvant therapeutic approaches for LAM in clinic.

摘要