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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：
10609457
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10609457
关键词：
Acceleration Actins Address Adjuvant Affect Age Aging Alleles Alveolar Antiestrogen Therapy Applications Grants Biomedical Research Cells Characteristics Clinic Cyst Data Diagnosis Disease Disease Progression Epithelium Estrogen Antagonists Estrogen Receptor alpha Estrogen Receptors Estrogens FDA approved FGF7 gene FRAP1 gene Female Future Genes 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 Pneumothorax 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 functional decline gain of function improved in vivo insight lung lesion 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

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited.

如果抑制硫氧还蛋白还原酶，则在结核性硬化基因突变的抗凋亡环境中活化的p53会导致细胞死亡。

DOI：
10.1007/s10495-021-01670-4
发表时间：
2021-06
期刊：
Apoptosis : an international journal on programmed cell death
影响因子：
0
作者：
Abdelwahab EMM;Bovari-Biri J;Smuk G;Fillinger J;McPhail D;Krymskaya VP;Pongracz JE
通讯作者：
Pongracz JE

Normalization of Enzyme Expression and Activity Regulating Vitamin A Metabolism Increases RAR-Beta Expression and Reduces Cellular Migration and Proliferation in Diseases Caused by Tuberous Sclerosis Gene Mutations.

DOI：
10.3389/fonc.2021.644592
发表时间：
2021
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Abdelwahab EMM;Bovari-Biri J;Smuk G;Harko T;Fillinger J;Moldvay J;Krymskaya VP;Pongracz JE
通讯作者：
Pongracz JE