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:
  • 金额:
    $ 48.83万
  • 依托单位:
  • 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

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。
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:
  • 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
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VERA P KRYMSKAYA其他文献

VERA P KRYMSKAYA的其他文献

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{{ truncateString('VERA P KRYMSKAYA', 18)}}的其他基金

Novel Combination Therapy for Treatment and Prevention of PulmonaryLymphangioleiomyomatosis (LAM) and Tuberous Sclerosis Complex (TSC)
治疗和预防肺淋巴管平滑肌瘤病 (LAM) 和结节性硬化症 (TSC) 的新型联合疗法
  • 批准号:
    10697901
  • 财政年份:
    2023
  • 资助金额:
    $ 48.83万
  • 项目类别:
mTORC1 and WNT in lung mesenchyme
肺间质中的 mTORC1 和 WNT
  • 批准号:
    10435544
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
mTORC1 and WNT in lung mesenchyme
肺间质中的 mTORC1 和 WNT
  • 批准号:
    10278071
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
Nitazoxanide as a Novel Therapy for Rare Disease Lymphangioleiomyomatosis and Tuberous Sclerosis
硝唑尼特作为罕见疾病淋巴管平滑肌瘤病和结节性硬化症的新疗法
  • 批准号:
    10258194
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
mTORC1 and WNT in lung mesenchyme
肺间质中的 mTORC1 和 WNT
  • 批准号:
    10634760
  • 财政年份:
    2021
  • 资助金额:
    $ 48.83万
  • 项目类别:
mTOR signaling in lung homeostasis, aging and disease
mTOR 信号在肺稳态、衰老和疾病中的作用
  • 批准号:
    10394731
  • 财政年份:
    2020
  • 资助金额:
    $ 48.83万
  • 项目类别:
mTOR signaling in lung homeostasis, aging and disease
mTOR 信号在肺稳态、衰老和疾病中的作用
  • 批准号:
    10163904
  • 财政年份:
    2020
  • 资助金额:
    $ 48.83万
  • 项目类别:
Urokinase-type plasminogen activator (uPA) in pathogenesis of lymphangioleiomyomatosis (LAM)
尿激酶型纤溶酶原激活剂 (uPA) 在淋巴管平滑肌瘤病 (LAM) 发病机制中的作用
  • 批准号:
    10323035
  • 财政年份:
    2019
  • 资助金额:
    $ 48.83万
  • 项目类别:
Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)
肺淋巴管平滑肌瘤病 (LAM) 中的淋巴管生成
  • 批准号:
    9242060
  • 财政年份:
    2016
  • 资助金额:
    $ 48.83万
  • 项目类别:
Lymphangiogenesis in Pulmonary Lymphangioleiomyomatosis (LAM)
肺淋巴管平滑肌瘤病 (LAM) 中的淋巴管生成
  • 批准号:
    9078976
  • 财政年份:
    2016
  • 资助金额:
    $ 48.83万
  • 项目类别:

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由两类细菌肌动蛋白 MreB 驱动的新型运动系统
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肌动蛋白和肌动蛋白结合蛋白的结构/相互作用
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