Mesenchymal Stromal Cells Modulate Intestinal Mesenteric Endothelium Via Hydrogen Sulfide

间充质基质细胞通过硫化氢调节肠系膜内皮

• 批准号: 10158481
• 负责人: TROY A MARKEL
• 金额: $ 15.03万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158481
• 关键词: Advisory Committees; Apoptosis; Award; Blood Vessels; Blood flow; Bone Marrow; Cell Death; Cells; Consultations; Cysteine; Data; Development Plans; Efferent Pathways; Emergency Situation; Endothelium; Enzymes; Exhibits; Funding; Future; Gases; Goals; Grant; Greater sac of peritoneum; Growth Factor; Gut Mucosa; Human; Hydrogen Sulfide; Hypotension; Inflammation; Injury; Institution; International; Intestinal Mucosa; Intestines; Intra-abdominal; Ischemia; Ischemic Bowel Disease; Leukocytes; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Mesentery; Molecular; Mutant Strains Mice; Mutate; NOS3 gene; Necrosis; Nitric Oxide; Operative Surgical Procedures; Organ; Organ failure; Pathway interactions; Patients; Pediatric Surgical Procedures; Perforation; Perfusion; Permeability; Prevention; Production; Program Development; Property; Recovery; Regenerative Medicine; Relaxation; Reperfusion Injury; Research; Research Personnel; Research Training; Role; Scientist; Sepsis; Small Interfering RNA; Source; Stromal Cells; Surgeon; Testing; Therapeutic Uses; Time; Training; Training Programs; Transgenic Organisms; United States National Institutes of Health; Vasodilation; Work; authority; career; career development; design; education planning; experience; experimental study; improved; inflammatory disease of the intestine; innovation; ischemic injury; knockout animal; meetings; mesenchymal stromal cell; novel; novel therapeutics; paracrine; prevent; professor; public health relevance; stem cell biology; stem cell therapy; symposium

PROJECT SUMMARY This new investigator proposal describes a 4 year training program for the development of a surgeon scientist career in Pediatric Surgery. The main focus of this new investigator’s work is on stem cell biology and stem cell therapy for the treatment of end organ ischemia. He is currently an Assistant Professor of Surgery at the IUSOM. His career goals are to use this K08 award to support his commitment to develop as a highly skilled scientist and in the long term to transition to a successful, independent, NIH-funded surgeon scientist. The IUSOM has guaranteed the applicant 75% protected time to commit to his research effort. In addition to the time commitment, the institution has provided an ample start-up package for the applicant, which includes lab space, research funds, and ancillary support for 5 years. The cornerstone of the career development plan is an exemplary scientific advisory committee. The five scientists are from diverse backgrounds and each is considered an international authority in their field. They have a long track record of supporting young scientists and providing effective mentorship. The candidate, in close consultation with the committee, has outlined an education plan that includes additional coursework, weekly lab meetings, national conferences, and an organized research plan to complete his training. The proposal investigates the underlying mechanism associated with mesenchymal stromal cell mediated intestinal protection following ischemic injury. The applicant developed a novel hypothesis that proposes that end organ intestinal protection is mediated by the stromal cell release of hydrogen sulfide gas, which works through efferent pathways, such as eNOS, to promote improved mesenteric perfusion. In testing of this hypothesis, two aims are outlined. Aim 1 is to define the role of hydrogen sulfide as a key stromal cell paracrine mediator in facilitating host protection following intestinal I/R. Aim 2 then attempts to elucidate the downstream mechanism that hydrogen sulfide utilizes on the mesenteric endothelium to promote improved perfusion following ischemia. {The proposal investigates nitric oxide as such a mechanism, and looks to determine if improved perfusion is due to mesenteric vasodilation, improved endothelial barrier function, or decreased leukocyte trapping within the microvasculature. These data will serve as ample transition into mechanistic testing for a future R01, in which a specific cysteine residue on eNOS will be mutated in order to generate a transgenic mutant mouse for invivo testing.} In summary, this research and training proposal aim to understand the molecular mechanisms associated with stromal cell mediated intestinal protection following intestinal ischemia. The grant, in conjunction with an expert and experienced mentoring panel, as well as strong institutional support from the IUSOM, would provide a highly innovative, supportive platform for this young surgeon-scientist to finish his scientific training and make the transition to independent investigator in the field of stem cell therapy and regenerative medicine.

项目总结 这份新的研究人员提案描述了一项为期4年的外科科学家发展培训计划。 从事儿科外科工作。这位新研究人员的主要工作重点是干细胞生物学和干细胞 终末器官缺血的细胞治疗。他目前是麻省理工学院的外科助理教授 IUSOM。他的职业目标是用这个K08奖来支持他致力于发展成为一名高技能的 从长远来看，他将成为一名成功的、独立的、由美国国立卫生研究院资助的外科科学家。 IUSOM保证了申请人75%的受保护时间来致力于他的研究工作。除了……之外 时间承诺，该机构为申请者提供了充足的启动方案，其中包括 实验室空间、研究经费和5年的辅助支持。职业发展计划的基石 是一个模范的科学咨询委员会。这五位科学家来自不同的背景，每个人都是 被认为是各自领域的国际权威。他们在支持年轻科学家方面有着长期的记录。 并提供有效的指导。候选人在与委员会密切协商后，概述了一项 教育计划，包括额外的课程作业、每周的实验室会议、国家会议和 组织研究计划以完成他的培训。 该方案研究了与间充质基质细胞介导的潜在机制 缺血损伤后的肠道保护。申请人提出了一个新的假设，提出了 终末器官肠道保护是由基质细胞释放硫化氢气体介导的，这是有效的 通过内皮型一氧化氮合酶等传出通路促进肠系膜血流的改善。在这方面的测试中 假设，概述了两个目标。目标1是定义硫化氢作为关键基质细胞的作用 旁分泌介体在促进肠道I/R后宿主保护中的作用 硫化氢促进肠系膜内皮细胞功能改善的下游机制 脑缺血后再灌流。{该提案将一氧化氮作为这样一种机制进行研究，并期待 确定血流灌注的改善是由于肠系膜血管扩张、内皮屏障功能改善，还是 减少白细胞在微血管内的滞留。这些数据将作为充分的过渡 未来R01的机械测试，其中eNOS上的特定半胱氨酸残基将发生突变，以便 生成转基因突变小鼠用于体内测试。} 综上所述，这项研究和培训计划旨在了解与 基质细胞介导的肠缺血后的肠道保护。这笔赠款与一项 专家和经验丰富的指导小组，以及来自IUSOM的强有力的机构支持，将提供 为这位年轻的外科医生和科学家提供一个极具创新性和支持性的平台，以完成他的科学培训并使 向干细胞治疗和再生医学领域的独立研究人员过渡。

项目成果

Interleukin-6 Therapy Improves Intestinal Recovery Following Ischemia.

Interleukin-6 疗法可改善缺血后的肠道恢复。

• DOI: 10.1016/j.jss.2019.02.001
• 发表时间: 2019
• 期刊: The Journal of surgical research
• 作者: TeWinkel,JanP;Drucker,NatalieA;Morocho,BryantS;Shelley,WChristopher;Markel,TroyA
• 通讯作者: Markel,TroyA

Sildenafil as a Rescue Agent Following Intestinal Ischemia and Reperfusion Injury.

西地那非作为肠缺血和再灌注损伤后的救援剂。

• DOI: 10.1016/j.jss.2019.09.037
• 发表时间: 2020
• 期刊: The Journal of surgical research
• 作者: Moore,HannahM;Drucker,NatalieA;Hosfield,BrianD;Shelley,WChris;Markel,TroyA
• 通讯作者: Markel,TroyA

It's all in the milk: chondroitin sulfate as potential preventative therapy for necrotizing enterocolitis.

• DOI: 10.1038/s41390-020-01125-7
• 发表时间: 2021-05
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Knowles TA;Hosfield BD;Pecoraro AR;Li H;Shelley WC;Markel TA
• 通讯作者: Markel TA

New directions in necrotizing enterocolitis with early-stage investigators.

• DOI: 10.1038/s41390-020-1078-0
• 发表时间: 2020-08
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Markel TA;Martin CA;Chaaban H;Canvasser J;Tanner H;Denchik H;Good M
• 通讯作者: Good M

Human Mesenchymal Stem Cell Hydrogen Sulfide Production Critically Impacts the Release of Other Paracrine Mediators After Injury.

人类间充质干细胞硫化氢的产生严重影响受伤后其他旁分泌介质的释放。

• DOI: 10.1016/j.jss.2020.04.014
• 发表时间: 2020
• 期刊: The Journal of surgical research
• 作者: Markel,TroyA;Drucker,NatalieA;Jensen,AmandaR;Olson,KennethR
• 通讯作者: Olson,KennethR