Strategies to Prevent and Repair Thymic Microenvironment

预防和修复胸腺微环境的策略

基本信息

  • 批准号:
    6913677
  • 负责人:
  • 金额:
    $ 37.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-01 至 2007-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Post-BMT immune deficiency causes significant morbidity and mortality in BMT recipients. Most recipients of T-cell replete matched sibling or unrelated donor HSC grafts experience late post-BMT infections, Strategies are urgently needed to speed thymopoietic recovery. A major cause of post-BMT immune deficiency is the loss of thymopoietic capacity. Normal thymopoiesis depends on the interaction of the thymic stroma-derived receptors and ligands. Damage to thymic epithelial cells (TEC) by pre-BMT conditioning impairs the ability of the thymus to generate mature T lymphocytes after BMT. Our overall hypothesis is that thymic microenvironmental injury is the major limiting factor responsible for slow T cell immune reconstitution and function, as indicated by the predisposition of the recipient to experience late infections post-BMT. Specific cytokines have been shown to regulate the development and proliferation of epithelial cells, key components in the thymic microenvironment which are needed for effective thymopoiesis. Keratinocyte growth factor (KGF) is one such cytokine. Based on the model that TEC are targets for BMT-associated thymic damage, we hypothesized that KGF pre-treatment would prevent TEC damage after BMT. Our preliminary data indicate this to be the case. In this proposal, we will explore the mechanism(s) responsible for the effects of KGF on facilitating thymopoiesis in BMT recipients. Inhibition of p53 has been shown to protect mice from the lethal genotoxic stress induced by conditioning regimen injury. Our preliminary data indicate a p53 inhibitor speeds thymopoietic recovery in lethally irradiated recipients of allogeneic TCD BM. We will determine whether KGF and p53 inhibitors operate on non-overlapping pathways and thus may be additive or synergistic in protecting TEC against injury. Thymopoiesis is well-known to decline with age, beginning after puberty. The thymic microenvironment is severely disrupted in aging and that blocking sex steroid production normalizes thymopoiesis. We propose to determine whether pre-BMT chemical blockade of sex steroid production using LHRH analogues (agonist or antagonist) will speed thymopoietic recovery in young or aged BMT recipients subjected to intensive conditioning injury. Our specific aims are: 1. To determine the thymopoietic and peripheral T cell immune functional effects of TEC sparing agents that target epithelial cell proliferation, inhibit apoptotic cell death, or block the negative regulatory effects of endogenous hormones that disrupt thymopoiesis; 2. To determine whether intracellular pathways required for thymic microenvironmental development or radiation resistance are essential for protecting the thymus from the effects of conditioning regimen injury. These data will lead to clinical trials designed to protect the thymic microenvironment against chemoradiotherapy injury and augment thymopoiesis.
描述(由申请人提供): BMT后免疫缺陷导致BMT接受者显著的发病率和死亡率。大多数T细胞完全匹配的同胞或无关供体HSC移植物的受体经历BMT后的晚期感染,迫切需要策略来加速胸腺生成恢复。骨髓移植后免疫缺陷的一个主要原因是胸腺生成能力的丧失。正常的胸腺生成依赖于胸腺基质衍生受体和配体的相互作用。骨髓移植前条件对胸腺上皮细胞(TEC)的损伤损害了骨髓移植后胸腺产生成熟T淋巴细胞的能力。我们的总体假设是,胸腺微环境损伤是负责缓慢的T细胞免疫重建和功能的主要限制因素,如受者的易感性所示,经历BMT后的晚期感染。已显示特异性细胞因子调节上皮细胞的发育和增殖,上皮细胞是有效胸腺生成所需的胸腺微环境中的关键组分。角质细胞生长因子(KGF)就是这样一种细胞因子。基于TEC是BMT相关胸腺损伤的靶点的模型,我们假设KGF预处理可以预防BMT后TEC损伤。我们的初步数据表明情况确实如此。在本研究中,我们将探讨KGF促进骨髓移植受者胸腺生成的机制。抑制p53已显示出保护小鼠免受由预处理方案损伤诱导的致死性遗传毒性应激。我们的初步数据表明,p53抑制剂的速度在致死性照射的异基因TCD骨髓受体的胸腺造血恢复。我们将确定KGF和p53抑制剂是否作用于非重叠途径,从而在保护TEC免受损伤方面可能是相加的或协同的。众所周知,胸腺生成会随着年龄的增长而下降,从青春期开始。胸腺微环境在衰老中被严重破坏,阻断性类固醇的产生使胸腺生成正常化。我们建议,以确定是否预BMT化学封锁性类固醇生产使用LHRH类似物(激动剂或拮抗剂)将加速胸腺造血恢复在年轻或老年BMT受体受到强烈的条件损伤。我们的具体目标是:1.确定靶向上皮细胞增殖、抑制凋亡性细胞死亡或阻断破坏胸腺生成的内源性激素的负调节作用的TEC保留剂的胸腺生成和外周T细胞免疫功能作用; 2.确定胸腺微环境发育或辐射抗性所需的细胞内途径是否对保护胸腺免受预处理方案损伤的影响至关重要。这些数据将导致临床试验,旨在保护胸腺微环境免受放化疗损伤和增强胸腺生成。

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 }}

Bruce R Blazar其他文献

Challenges and solutions for cellular therapy development in autoimmune diseases
自身免疫性疾病中细胞治疗发展的挑战与解决方案
  • DOI:
    10.1016/s2665-9913(24)00274-1
  • 发表时间:
    2024-11-01
  • 期刊:
  • 影响因子:
    16.400
  • 作者:
    Elizabeth R Volkmann;John Varga;Bruce R Blazar;Steven Z Pavletic
  • 通讯作者:
    Steven Z Pavletic
Five-Year Outcomes of the “Abatacept Combined with a Calcineurin Inhibitor and Methotrexate for Graft Versus Host Disease (GVHD) Prophylaxis: A Randomized Controlled Trial” (‘ABA2‘)
  • DOI:
    10.1182/blood-2024-205130
  • 发表时间:
    2024-11-05
  • 期刊:
  • 影响因子:
  • 作者:
    Lev Gorfinkel;Muna Qayed;Brandi Bratrude;Kayla Betz;Kyle Hebert;Sung W. Choi;Jeffrey Davis;Christine Duncan;Roger H. Giller;Michael S. Grimley;Andrew Harris;David A Jacobsohn;Nahal Lalefar;Nosha Farhadfar;Michael A. Pulsipher;Shalini Shenoy;Aleksandra Petrovic;Kirk R. Schultz;Gregory Yanik;Bruce R Blazar
  • 通讯作者:
    Bruce R Blazar
IL-33 Induces Paneth Cell Production of EGF and Soluble ST2, Regulating Epithelial Regeneration after Intestinal Injury
  • DOI:
    10.1182/blood-2023-191189
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Marco Calafiore;YA-Yuan Fu;Paola Vinci;Viktor Arnhold;Winston Chang;Suze Jansen;Anastasiya Egorova;Shuichiro Takashima;Jason Kuttiyara;Takahiro Ito;Jonathan Serody;Susumu Nakae;Heth Turnquist;Johan van Es;Hans Clevers;Caroline A. Lindemans;Bruce R Blazar;Alan M. Hanash
  • 通讯作者:
    Alan M. Hanash
Cyclosporine and Voclosporin Resistant Immune Effector Cells to Improve Outcomes after Stem Cell Transplantation
  • DOI:
    10.1182/blood-2023-180218
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Holly Wobma;Jiayi Dong;Francesca Alvarez Calderon;Xianliang Rui;Katherine Michaelis;Bruce R Blazar;Victor Tkachev;Ulrike Gerdemann;Leslie Kean
  • 通讯作者:
    Leslie Kean
Mitochondrial Pyruvate Carrier Inhibition Mitigates Murine Chronic Graft Versus Host Disease By Attenuating the Germinal Center Reaction
  • DOI:
    10.1182/blood-2023-185200
  • 发表时间:
    2023-11-02
  • 期刊:
  • 影响因子:
  • 作者:
    Fathima A Mohamed;Stephanie Y Rhee;Joanna Ly;Ethan G Aguilar;Haley Melin;Peter T Sage;Tanner Schumacher;Govindarajan Thangavelu;Michael C Zaiken;Juan Liu;Venkatram Mereddy;Jason W Locasale;Bruce R Blazar
  • 通讯作者:
    Bruce R Blazar

Bruce R Blazar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('Bruce R Blazar', 18)}}的其他基金

University of Minnesota Clinical and Translational Science Institute (UMN CTSI)
明尼苏达大学临床与转化科学研究所 (UMN CTSI)
  • 批准号:
    10763967
  • 财政年份:
    2023
  • 资助金额:
    $ 37.13万
  • 项目类别:
In Vivo Prevention of Murine GVHD
小鼠 GVHD 的体内预防
  • 批准号:
    10362877
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
Metabolomics of cGVHD
cGVHD 的代谢组学
  • 批准号:
    10698171
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
In Vivo Prevention of Murine GVHD
小鼠 GVHD 的体内预防
  • 批准号:
    10610863
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
Metabolomics of cGVHD
cGVHD 的代谢组学
  • 批准号:
    10493800
  • 财政年份:
    2022
  • 资助金额:
    $ 37.13万
  • 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
  • 批准号:
    10092348
  • 财政年份:
    2021
  • 资助金额:
    $ 37.13万
  • 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
  • 批准号:
    10560605
  • 财政年份:
    2021
  • 资助金额:
    $ 37.13万
  • 项目类别:
Exploiting the VISTA Pathway to Prevent Acute GVHD and Control Steroid Refractory Disease
利用 VISTA 途径预防急性 GVHD 和控制类固醇难治性疾病
  • 批准号:
    10348683
  • 财政年份:
    2021
  • 资助金额:
    $ 37.13万
  • 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
  • 批准号:
    10305635
  • 财政年份:
    2019
  • 资助金额:
    $ 37.13万
  • 项目类别:
Nongenotoxic conditioning for gene therapy and allogeneic transplantation in Fanconi anemia
范可尼贫血基因治疗和同种异体移植的非基因毒性调理
  • 批准号:
    10656502
  • 财政年份:
    2019
  • 资助金额:
    $ 37.13万
  • 项目类别:

相似海外基金

ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    6238317
  • 财政年份:
    1997
  • 资助金额:
    $ 37.13万
  • 项目类别:
CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
生物信号转导中的细胞粘附
  • 批准号:
    3732412
  • 财政年份:
  • 资助金额:
    $ 37.13万
  • 项目类别:
ROLE OF CELL ADHESION IN BIOLOGICAL SIGNAL TRANSDUCTION
细胞粘附在生物信号转导中的作用
  • 批准号:
    5210031
  • 财政年份:
  • 资助金额:
    $ 37.13万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了