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.

项目摘要 这个新的研究者建议描述了一项为期4年的外科医生科学家的培训计划 小儿手术的职业。这项新研究者工作的主要重点是干细胞生物学和茎 细胞疗法用于治疗终端器官缺血。他目前是手术助理教授 iusom。他的职业目标是利用这个K08奖，以支持他发展为高技能的承诺 科学家，长期过渡到成功，独立，NIH资助的外科医生科学家。 IUSOM保证了申请人75％的保护时间，以致力于他的研究工作。此外 时间的承诺，该机构为申请人提供了足够的启动套餐，其中包括 实验室空间，研究基金和辅助支持已有5年。职业发展计划的基石 是一个典范科学咨询委员会。这五位科学家来自潜水员，每个科学家都是 被认为是其领域的国际权威。他们有支持年轻科学家的悠久记录 并提供有效的心态。候选人在与委员会密切协商下概述了 教育计划包括其他课程，每周实验室会议，国家会议和 有组织的研究计划以完成他的培训。 该提案研究了与间充质基质细胞介导的基本机制 缺血性损伤后的肠道保护。申请人提出了一个新的假设，该假设提出 最终器官肠道保护是由硫化氢气体的基质细胞释放介导的 通过有效的途径，例如eNOS，可以促进肠系膜灌注的改善。在测试中 假设，概述了两个目标。目的1是将硫化氢作为关键基质细胞的作用 在肠道I/R之后支持宿主保护的旁分泌介体。 AIM 2然后尝试阐明 硫化氢在肠系膜原始座上利用氢的下游机制促进了改善 灌注以下缺血。 {该提案将一氧化氮作为一种机制进行调查，并希望 确定是否改善灌注是由于肠系膜血管舒张，改善的内皮屏障功能或 微脉管系统内的白细胞捕获减少。这些数据将是足够的过渡到 对未来R01的机械测试，其中特定的半胱氨酸在eNOS上的保留将被突变为 生成用于Invivo测试的转基因突变小鼠。} 总而言之，该研究和培训建议旨在了解与 肠缺血后基质细胞介导的肠道保护。这笔赠款与 专家和经验丰富的心理小组以及IUSOM的强大机构支持将提供 对于这位年轻的外科医生科学家来说，这是一个高度创新，支持的平台，可以完成他的科学培训并进行 在干细胞疗法和再生医学领域的独立研究者的过渡。

项目成果

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

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

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

The assessment of microbiome changes and fecal volatile organic compounds during experimental necrotizing enterocolitis.

• DOI: 10.1016/j.jpedsurg.2021.02.043
• 发表时间: 2021-06
• 期刊: Journal of pediatric surgery
• 影响因子: 2.4
• 作者: Hosfield BD;Drucker NA;Pecoraro AR;Shelley WC;Li H;Baxter NT;Hawkins TB;Markel TA
• 通讯作者: Markel TA

Stem Cell Therapy and Hydrogen Sulfide: Conventional or Nonconventional Mechanisms of Action?

• DOI: 10.1097/shk.0000000000001420
• 发表时间: 2020-06-01
• 期刊: SHOCK
• 影响因子: 3.1
• 作者: Jensen, Amanda R.;Drucker, Natalie A.;Markel, Troy A.
• 通讯作者: Markel, Troy A.