Combined effects of aging and type 2 diabetes on wound healing in a humanized mouse model

衰老和 2 型糖尿病对人源化小鼠模型伤口愈合的综合影响

基本信息

项目摘要

Abstract Aging is a powerful risk factor for the development of chronic, non-healing foot ulcers in people with type 2 diabetes (T2DM). Diabetic foot ulcers in older adults with T2DM have devastating consequences, leading to increased risks of amputation and all-cause mortality. There is a compelling, unmet need to develop therapies to treat these non-healing wounds in this population; however, an appropriate animal model for use in the development of biotherapeutics and stem cell therapies with a high degree of translatability to human disease does not exist. Therefore, the overall goal of this proposal is to develop an aged-T2DM humanized mouse model to study the mechanisms by which the combined effects of aging and T2DM dysregulate the human immune system of T2DM patients during wound healing and to test therapeutics based on these new insights. To achieve this goal, two Specific Aims are proposed. The purpose of Specific Aim 1 is to develop a humanized mouse model engrafted with CD34+ hematopoietic stem cells (HSCs) from aged-T2DM human donors to study wound healing. The hypothesis is that humanized mice engrafted with CD34+ HSCs from older adults with diabetes faithfully recapitulate the non-healing wound phenotype and skewed polarization of wound- infiltrating macrophages that has been documented in human T2DM patients. This model is based on our published and unpublished findings that T2DM and aging impair wound healing by an oxidant stress- dependent HSC autonomous mechanism. Thus, the aging-T2DM-associated impairment in wound healing will be conferred by the donor HSCs from aged-T2DM patients. The purpose of Specific Aim 2 is to determine the effect of ATLAS therapy on wound healing in humanized mice engrafted with aged-T2DM HSCs. The hypothesis is that ATLAS treatment of HSCs derived from aged T2DM human donors prior to engraftment into NSG-SGM3 mice reduces HSC oxidant stress and increases nitric oxide bioavailability that restores normal macrophage number and polarization in wounds. Our results show that in a T2DM murine model of wound healing ATLAS, a combination of L-arginine, tetrahydrobiopterin, and L-ascorbate, decreases HSC oxidative stress and increases HSC NO bioavailability that restores normal wound healing. The development of the proposed humanized mouse model bridges a major gap between murine wound healing models and human non-healing foot ulcers in older adults with T2DM; thus, the creation of a highly translatable tool to develop novel biological therapies to treat non-healing wounds in older adults with T2DM fulfills a major unmet need for these patients. As a consequence of the results of this project, we hope to greatly reduce the suffering from this devasting problem that disproportionately affects older adults worldwide.
摘要

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Louis Michael Messina其他文献

Louis Michael Messina的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Louis Michael Messina', 18)}}的其他基金

Hypercholesterolemia Impairs Stem Cell-Mediated Post-Ischemic Neovascularization
高胆固醇血症损害干细胞介导的缺血后新血管形成
  • 批准号:
    9084611
  • 财政年份:
    2014
  • 资助金额:
    $ 20.94万
  • 项目类别:
Hypercholesterolemia Impairs Stem Cell-Mediated Post-Ischemic Neovascularization
高胆固醇血症损害干细胞介导的缺血后新血管形成
  • 批准号:
    8890880
  • 财政年份:
    2014
  • 资助金额:
    $ 20.94万
  • 项目类别:
Hypercholesterolemia Impairs Stem Cell-Mediated Post-Ischemic Neovascularization
高胆固醇血症损害干细胞介导的缺血后新血管形成
  • 批准号:
    8764380
  • 财政年份:
    2014
  • 资助金额:
    $ 20.94万
  • 项目类别:
OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA
ENOS 在严重肢体缺血中的过度表达
  • 批准号:
    6711255
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
Mesenchymal stem cells in the treatment of hindlimb ischemia in diabetic mice
间充质干细胞治疗糖尿病小鼠后肢缺血
  • 批准号:
    8463583
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA
ENOS 在严重肢体缺血中的过度表达
  • 批准号:
    7417446
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA
ENOS 在严重肢体缺血中的过度表达
  • 批准号:
    7179321
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
Mesenchymal stem cells in the treatment of hindlimb ischemia in diabetic mice
间充质干细胞治疗糖尿病小鼠后肢缺血
  • 批准号:
    7987780
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA
ENOS 在严重肢体缺血中的过度表达
  • 批准号:
    6837663
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:
OVEREXPRESSION OF ENOS IN CRITICAL LIMB ISCHEMIA
ENOS 在严重肢体缺血中的过度表达
  • 批准号:
    7058205
  • 财政年份:
    2004
  • 资助金额:
    $ 20.94万
  • 项目类别:

相似海外基金

Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
  • 批准号:
    495182
  • 财政年份:
    2023
  • 资助金额:
    $ 20.94万
  • 项目类别:
Investigating how alternative splicing processes affect cartilage biology from development to old age
研究选择性剪接过程如何影响从发育到老年的软骨生物学
  • 批准号:
    2601817
  • 财政年份:
    2021
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Studentship
RAPID: Coronavirus Risk Communication: How Age and Communication Format Affect Risk Perception and Behaviors
RAPID:冠状病毒风险沟通:年龄和沟通方式如何影响风险认知和行为
  • 批准号:
    2029039
  • 财政年份:
    2020
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Standard Grant
Neighborhood and Parent Variables Affect Low-Income Preschool Age Child Physical Activity
社区和家长变量影响低收入学龄前儿童的身体活动
  • 批准号:
    9888417
  • 财政年份:
    2019
  • 资助金额:
    $ 20.94万
  • 项目类别:
The affect of Age related hearing loss for cognitive function
年龄相关性听力损失对认知功能的影响
  • 批准号:
    17K11318
  • 财政年份:
    2017
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9320090
  • 财政年份:
    2017
  • 资助金额:
    $ 20.94万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    10166936
  • 财政年份:
    2017
  • 资助金额:
    $ 20.94万
  • 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
  • 批准号:
    9761593
  • 财政年份:
    2017
  • 资助金额:
    $ 20.94万
  • 项目类别:
How age dependent molecular changes in T follicular helper cells affect their function
滤泡辅助 T 细胞的年龄依赖性分子变化如何影响其功能
  • 批准号:
    BB/M50306X/1
  • 财政年份:
    2014
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Training Grant
Inflamm-aging: What do we know about the effect of inflammation on HIV treatment and disease as we age, and how does this affect our search for a Cure?
炎症衰老:随着年龄的增长,我们对炎症对艾滋病毒治疗和疾病的影响了解多少?这对我们寻找治愈方法有何影响?
  • 批准号:
    288272
  • 财政年份:
    2013
  • 资助金额:
    $ 20.94万
  • 项目类别:
    Miscellaneous Programs
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了