Aging and IGF-1 Receptor in a three dimensional matrix

Summary

Principal Investigator: Itay Bentov
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2012-08-15 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Anesthesia, microcirculation, and wound repair in aging
    Itay Bentov
    From the Department of Anesthesiology and Pain Medicine I B and Division of Gerontology and Geriatric Medicine, Department of Medicine M J R, Harborview Medical Center, University of Washington, Seattle, Washington
    Anesthesiology 120:760-72. 2014

Research Grants

  1. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  3. Assessment of Corneal Fibroblast Biomechanical Behavior
    W Matthew Petroll; Fiscal Year: 2013
  4. Biobehavioral Foundations and Development of Cognitive Competence
    David A Washburn; Fiscal Year: 2013
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
  6. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
  7. Integrative Analysis of Longitudinal Studies of Aging
    Andrea M Piccinin; Fiscal Year: 2013
  8. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
  9. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  10. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc Anesthesia, microcirculation, and wound repair in aging
    Itay Bentov
    From the Department of Anesthesiology and Pain Medicine I B and Division of Gerontology and Geriatric Medicine, Department of Medicine M J R, Harborview Medical Center, University of Washington, Seattle, Washington
    Anesthesiology 120:760-72. 2014
    ..The authors examined the role of anesthetic management in optimizing the microcirculation and potentially improving postoperative wound repair in older persons. ..

Research Grants30

  1. Glycan Modulation of Inflammatory Responses
    Ajit P Varki; Fiscal Year: 2013
    ..abstract_text> ..
  2. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  3. Assessment of Corneal Fibroblast Biomechanical Behavior
    W Matthew Petroll; Fiscal Year: 2013
    ..During the course of the grant, training will be provided to a total of two biomedical engineering graduate (PhD) students, two post-docs, as well as 4 summer medical students and 3 undergraduate research fellows. ..
  4. Biobehavioral Foundations and Development of Cognitive Competence
    David A Washburn; Fiscal Year: 2013
    ..RELEVANCE: The findings of these projects will advance our understanding of cognition and its disorders, generating educational interventions and clinical applications with relevance to a wide range of mental health issues. ..
  5. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....
  6. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  7. Integrative Analysis of Longitudinal Studies of Aging
    Andrea M Piccinin; Fiscal Year: 2013
    ..abstract_text> ..
  8. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  9. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  10. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  11. siRNA-gold nanoparticle mediated ganglioside depletion for diabetic wound healing
    AMY SUSAN PALLER; Fiscal Year: 2013
    ..These studies promise to have great impact in the treatment of wounds in humans, particularly in individuals with insulin-resistant diabetes. ..
  12. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  13. Development of Adult Pluripotent Very Small Embryonic Like (VSEL) Stem Cells to T
    DENIS OVEREND RODGERSON; Fiscal Year: 2013
    ....
  14. Transforming Growth Factor-Beta (TGF-b) Signaling in Aged Skin
    Taihao Quan; Fiscal Year: 2013
    ..This hypothesis is novel because it focuses on the importance of the extracellular matrix, rather than inherent cellular deficits, as a driving force for the aging process in humans. ..
  15. New Approaches To Cardiothoracic Tolerance Induction
    Joren C Madsen; Fiscal Year: 2013
    ..We anticipate ongoing progress will continue to contribute to a reduction in the morbidity and mortality associated with solid organ transplantation. ..
  16. Molecular Engineering of Damaged Myocardium To Enhance Regeneration And Repair
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The long term goal will be to transfer the Fn fragment expressing AAV9 regimen into human disease establishing an innovative therapeutic concept for regenerative medicine. ..
  17. Mechanisms of Microvascular Control and Coordination in Health and Disease
    Gerald A Meininger; Fiscal Year: 2013
    ..End of Abstract) ..
  18. The Pharmacology of Dermal Fibrosis
    Bruce Neil Cronstein; Fiscal Year: 2013
    ....