[R01] Sex Dimorphism in Age-Related Knee Osteoarthritis
Ente: National Institute on Aging
Scadenza: 2028-05-31
Importo max: 574.423 EUR
Paese: US
Descrizione
ABSTRACT
As indicated by the 2019 Global Burden of Disease Study, although women, on average, have a longer lifespan
than men, women typically experience worsened health outcomes as they age. Notably, postmenopausal women
have a higher incidence of knee osteoarthritis (KOA) and present with more severe disease progression over
time. However, it is still unclear whether these differences are genetic in nature, hormonal in nature, or a
combination of the two. Here, we propose to investigate whether and how changes in the chondrocyte
microenvironment—including soluble factors (Aim1) and extracellular matrix (ECM) stiffening (Aim2)—drive
KOA pathogenesis in a sex- and age-dependent manner. Specifically, in Aim 1, we will mechanistically
interrogate the direct role of soluble microenvironmental factors on the loss of cartilage integrity with aging and
according to sex. In Aim 2, we will interrogate the contribution of ECM biophysical properties on the loss of
cartilage integrity with aging and according to sex. We will accomplish these aims using technically innovative
approaches, including: (1) an in vitro and in vivo heterosex biofluid exchange model, which will allow us to
disentangle the multi-dimensional contribution of environmental factors on chondrocyte health and cartilage
integrity over time; (2) an advanced network medicine approach integrated with machine learning algorithms to
elucidate the sex chromosome- and sex hormone-dependent regulatory landscape; and (3) a physiologically
relevant model of female aging by which menopause is chemically-induced in middle-aged mice. These
conceptually and technically innovative studies will be carried out by an interdisciplinary team comprising a
stem cell biologist (PI), a computational biologist (co-PI), and a bioengineer (co-I), the breadth of which
enhances feasibility, impact, and likelihood for success. Successful completion of the aims as proposed will
provide mechanistic insights into how sex profiles impact cartilage physiology over time. Ultimately, we
anticipate that the innovative research studies proposed will aid in the development of effective interventions
that consider sex-specific variables to the benefit of our aging population.
Istituzione: SPAULDING REHABILITATION HOSPITAL
PI: Fabrisia Ambrosio, Hirotaka Iijima
Progetto: 5R01AG089455-03
Settori: National Institute on Aging
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