The Reduction of NLRX1 and Its Role in Pulmonary Aging

Information

  • Research Project
  • 10490541
  • ApplicationId
    10490541
  • Core Project Number
    R56AG053495
  • Full Project Number
    2R56AG053495-06
  • Serial Number
    053495
  • FOA Number
    PA-19-056
  • Sub Project Id
  • Project Start Date
    8/15/2016 - 8 years ago
  • Project End Date
    8/31/2022 - 2 years ago
  • Program Officer Name
    KERR, CANDACE L
  • Budget Start Date
    9/30/2021 - 3 years ago
  • Budget End Date
    8/31/2022 - 2 years ago
  • Fiscal Year
    2021
  • Support Year
    06
  • Suffix
  • Award Notice Date
    9/23/2021 - 3 years ago
Organizations

The Reduction of NLRX1 and Its Role in Pulmonary Aging

PROJECT SUMMARY The expansion of the elderly population has profound implications for society. In medicine, chronic diseases affect older adults disproportionately, rendering aging itself a root of disability, reduced quality of life and increased health care costs. Biological aging of the pulmonary system (lung aging) is no exception. Lung aging is associated with structural changes that lead to a progressive decline in function and is one of the major risk factors of chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Our knowledge of the molecular mechanisms in lung aging, however, remains inadequate. Recent publications including ours highlight the significance of NLRX1 as a regulator of innate and adaptive immunity, inflammation and tumorigenesis. We demonstrated that a mitochondrial molecule, nucleotide-binding domain and leucine-rich-repeat-containing protein X1 (NLRX1), plays a critical role in COPD pathogenesis. Our recent studies revealed that NLRX1 decreases with age, mostly in pulmonary macrophages, in murine lungs. In addition, 24-month-old (mo) NLRX1 null mutant (-/-) mice manifested enhanced characteristics of functional and molecular alterations observed in lung aging; these features included (a) decrease of NAD+/NADH ratio, (b) activation of mTOR signaling, (c) increase of cellular senescence, (d) activation of inflammasomes signaling, and (e) enhancement of senile lung- like alveolar remodeling, all of which were only modestly observed in lungs from wild type (WT) controls. Intriguingly, the cells that contain the NLRX1 molecule with a modified c-terminal end revealed impairment of NLRX1 function, hinting mechanistic insight at the molecular level. Moreover, in vivo treatment with rapamycin, a known mTOR inhibitor, induced the expression of NLRX1, suggesting the existence of a feed-forward loop wherein aging-associated mTOR activation may further suppress NLRX1 in vivo. This constellation of findings led us to hypothesize that NLRX1 and mTOR signaling reciprocally regulate each other and the NLRX1-NAD+- mTOR axis plays a critical role in lung aging in vivo. Specifically, the following aims are proposed: Aim #1. Define the physiologic significance of the NLRX1-NAD+-mTOR axis contribution to lung aging in vivo. Aim #2. Elucidate the underlying mechanism(s) by which mTOR signaling mediates a reciprocal regulation of NLRX1 expression. Aim #3. Determine the functional significance of the c-terminal end of the NLRX1 molecule in the lung aging process. Recently, it has been noted that many pivotal molecular features of aging biology are also found to contribute to the pathogenesis of chronic lung disorders such as COPD and idiopathic pulmonary fibrosis (IPF), for which advanced age is the most important risk factor. Thus, an enhanced understanding of the lung aging process has paramount significance and may provide an opportunity for the development of novel therapeutics for these major unmet medical needs. The current application seeks to identify a previously unprecedented molecular mechanism by which NLRX1 contributes to the biology of lung aging.

IC Name
NATIONAL INSTITUTE ON AGING
  • Activity
    R56
  • Administering IC
    AG
  • Application Type
    2
  • Direct Cost Amount
    204999
  • Indirect Cost Amount
    138374
  • Total Cost
    343373
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    866
  • Ed Inst. Type
    SCHOOLS OF MEDICINE
  • Funding ICs
    NIA:343373\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ASG
  • Study Section Name
    Aging Systems and Geriatrics Study Section
  • Organization Name
    YALE UNIVERSITY
  • Organization Department
    INTERNAL MEDICINE/MEDICINE
  • Organization DUNS
    043207562
  • Organization City
    NEW HAVEN
  • Organization State
    CT
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    065208327
  • Organization District
    UNITED STATES