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Wounding Therapy and Photocarcinogenesis

创伤治疗和光致癌

基本信息

批准号：
10704206
负责人：
DAN F SPANDAU
金额：
$ 45.07万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704206
关键词：
Actinic keratosis Acute Aftercare Age Chemopreventive Agent Clinical Trials Compensation DNA Damage DNA Repair Data Dermabrasion Dermal Dermis Disease Elderly Ensure Environmental Risk Factor Epidermis Exposure to Female Fibroblasts Financial Hardship Forearm Genotoxic Stress Goals Grant Healthcare Systems Human In Vitro Incidence Individual Induction of Apoptosis Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor Intervention Knowledge Laboratories Lasers Longevity Malignant Neoplasms Mediating Monitor Neoplasms Outcome Study Patients Population Populations at Risk Postmenopause Predisposition Process Production Productivity Proliferating Publishing Receptor Activation Receptor Signaling Rejuvenation Risk Risk Factors Role Skin Skin Aging Skin Cancer Skin Carcinoma Source Sunlight Survival Rate Testing Therapeutic Therapeutic Intervention Tumor Escape UV carcinogenesis UV induced UV protection UVB induced Underserved Population United States Wrist aged cancer diagnosis carcinogenesis carcinogenicity design epidemiologic data genome-wide analysis high risk imaging platform in vivo irradiation keratinocyte neoplastic cell non-invasive imaging novel novel imaging technology novel therapeutic intervention premalignant prevent prophylactic recruit repaired response senescence single-cell RNA sequencing skin barrier skin wound transcriptomics ultraviolet wound wound treatment

项目摘要

ABSTRACT Non-melanoma skin cancer (NMSC) is a disease primarily afflicting geriatric patients as evidenced by the fact that 80% of all non-melanoma skin cancers are diagnosed in patients over the age of 60 years. As such, geriatric skin responds to cancer-inducing ultraviolet B (UVB) irradiation in a manner that allows the establishment of tumor cells. While the correlation between aged epidermis and skin cancer is obvious, the mechanism responsible for this relationship remains obscure. Recent in vitro evidence as well as epidemiological data suggests one possible mechanism may involve alterations in the insulin-like growth factor-1 receptor (IGF-1R) signaling network. Using normal human keratinocytes grown in vitro, activated IGF- 1Rs protect keratinocytes from UVB-induced apoptosis; however, while UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication, in fact they are senescent. The critically important observation was that in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate. In the skin, keratinocytes express the IGF-1R but they do not synthesize IGF-1. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. Interestingly, as dermal fibroblasts age, their capacity to produce IGF-1 is severely diminished; therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1 and a concomitant reduction in IGF-1R activation. We have demonstrated that geriatric skin responds to UVB irradiation in a manner that could lead to initiated carcinogenic keratinocytes. This inappropriate UVB response can be corrected by treatment with exogenous IGF-1. Furthermore, we have shown that treatment of geriatric skin with non-ablative dermal rejuvenation therapies can re-establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on geriatric skin. Moreover, we have demonstrated this protection to acute UVB exposure is durable for up to two years. In this proposal, we will continue and expand our ongoing clinical trials on the prophylactic effect of non-ablative wounding therapies to both treat and prevent UVB-induced skin cancer. In particular, we will recruit post-menopausal females for these studies as this is an underserved population for skin cancer studies. A novel non-invasive mesoscopic imaging platform will be used to monitor actinic neoplasia progression. In addition, we will examine the mechanisms responsible for the ability of non-ablative wounding therapies to increase fibroblast-associated IGF-1 expression. These studies will have a major impact on the treatment of NMSC by establishing a novel anti-carcinogenic role for dermal wounding. Furthermore, the data from these studies will confirm a new paradigm defining the mechanism of age-associated skin cancer. Outcomes for these studies include novel therapeutic strategies as well as non-invasive imaging platforms to monitor field carcinogenesis in at risk-populations.

摘要

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes.

DOI：
10.1091/mbc.e17-06-0362
发表时间：
2018-01-01
期刊：
Molecular biology of the cell
影响因子：
3.3
作者：
Collier AE;Spandau DF;Wek RC
通讯作者：
Wek RC

Impact of Age and Insulin-Like Growth Factor-1 on DNA Damage Responses in UV-Irradiated Human Skin.

DOI：
10.3390/molecules22030356
发表时间：
2017-02-26
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
Kemp MG;Spandau DF;Travers JB
通讯作者：
Travers JB

Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2.

DOI：
10.1016/j.jid.2017.04.029
发表时间：
2017-09
期刊：
The Journal of investigative dermatology
影响因子：
0
作者：
Collier AE;Wek RC;Spandau DF
通讯作者：
Spandau DF

Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.

DOI：
10.1016/j.molonc.2016.06.002
发表时间：
2016-10
期刊：
Molecular oncology
影响因子：
6.6
作者：
Loesch MM;Collier AE;Southern DH;Ward RE;Tholpady SS;Lewis DA;Travers JB;Spandau DF
通讯作者：
Spandau DF

Fibronectin Promotes Wound Healing in an Atopic Human Skin Xenografting Model.

纤连蛋白促进特应性人类皮肤异种移植模型中的伤口愈合。