Age-associated differences in tissue repair are regulated, in part, by Insulin like Growth Factor 1 (IGF-1). The effects of IGF-1 are mediated by Insulin like Growth Factor-1 Receptor (IGF1R), a ubiquitous cell-surface receptor. Several lines of evidence suggest a functional relationship between expression and activation of the IGF1R and skin aging, which results in increased susceptibility to injury and reduced wound healing. For example, IGF1R signaling plays a critical role in the interaction of dermal fibroblasts with th extracellular matrix during wound repair. Oxidative stress, which increases in aged tissues and during the response to injury, induces p53 expression. p53, in turn, reduces IGF1R expression and activation. The principal extracellular matrix component of skin is collagen I. In the skin, collagen I surrounds dermal fibroblasts in a 3 dimensional arrangement that confers stability and regulates function. Collagen extracted from the tail tendons of mice can be polymerized into a 3-dimensional (3D) matrix that mimics the properties of dermal collagen in vivo. We propose to utilize this well characterized 3D collagen matrix to study the influence of aging on IGF1R. Our hypothesis is that aged human dermal fibroblasts, relative to young fibroblasts, have reduced expression of IGF1R that results in decreased proliferation and migration. We further hypothesize that these changes can be reversed by activation of the IGF1R with IGF-1 and/or inhibiting p53 expression. To address these hypotheses we propose the following specific aims:
Aim 1. To define if reduced IGF1R expression and activation in aged fibroblasts inhibits their proliferation, migration, and contractile function in a 3D collagen matrix.
Aim 2. To determine if p53 inhibition increases IGF1R expression and activation in aged fibroblasts in a 3D collagen matrix. If successful, the results from this study of fibroblast behavior in a well-characterized 3 collagen matrix will clarify the role of IGF1R age-associated changes on functions of dermal fibroblasts relevant to tissue repair. This is significant because understanding the basis of age-associated delayed wound healing could potentially offer novel therapeutic modalities.

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My goal is to use my background in IGF-1 to define fibroblast behaviors that are relevant to impaired wound healing in aging. Utilizing a three dimensional collagen matrix, baseline IGF1R expression in aged and young fibroblasts will be measured. Fibroblast responses to IGF-1 stimulation and p53 inhibition will be elucidated.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Small Research Grants (R03)
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Special Emphasis Panel (ZAG1-ZIJ-9 (M1))
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Williams, John
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University of Washington
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Bentov, Itay; Damodarasamy, Mamatha; Spiekerman, Charles et al. (2016) Lidocaine Impairs Proliferative and Biosynthetic Functions of Aged Human Dermal Fibroblasts. Anesth Analg 123:616-23
Bentov, Itay; Reed, May J (2015) The effect of aging on the cutaneous microvasculature. Microvasc Res 100:25-31
Bentov, Itay; Damodarasamy, Mamatha; Plymate, Stephen et al. (2014) Decreased proliferative capacity of aged dermal fibroblasts in a three dimensional matrix is associated with reduced IGF1R expression and activation. Biogerontology 15:329-37
Bentov, Itay; Reed, May J (2014) Anesthesia, microcirculation, and wound repair in aging. Anesthesiology 120:760-72