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 这份新的研究者提案描述了一个为期4年的外科医生科学家发展培训计划 小儿外科的职业生涯。这位新研究者的主要工作重点是干细胞生物学和干细胞 用于治疗终末器官缺血的细胞疗法。他目前是外科助理教授， IUSOM。他的职业目标是利用K 08奖项来支持他发展成为高技能人才的承诺 科学家，并在长期过渡到一个成功的，独立的，NIH资助的外科医生科学家。 IUSOM保证申请人有75%的时间致力于研究工作。除了 为了节省时间，院校为申请人提供了一套充足的起步计划，包括 5年的实验室空间、研究资金和辅助支持。职业发展计划的基石 是一个模范的科学顾问委员会。这五位科学家来自不同的背景， 被认为是该领域的国际权威。他们在支持年轻科学家方面有着悠久的历史 提供有效的指导。候选人在与委员会密切磋商后，概述了一个 教育计划，包括额外的课程，每周实验室会议，全国会议，和一个 组织研究计划来完成他的训练。 该提案研究了与间充质基质细胞介导的 缺血性损伤后的肠道保护。申请人提出了一个新的假设， 终末器官肠道保护是由基质细胞释放硫化氢气体介导的， 通过传出途径，如eNOS，促进改善肠系膜灌注。在测试中， 假设，两个目标概述。目的1是确定硫化氢作为关键基质细胞的作用 旁分泌介质促进肠道I/R后宿主保护。目标2然后试图阐明 硫化氢利用肠系膜内皮细胞促进改善的下游机制 缺血后的灌注。{The该提案将一氧化氮作为这样一种机制进行研究，并期待 确定灌注改善是否是由于肠系膜血管舒张、内皮屏障功能改善，或 减少微血管内的白细胞捕获。这些数据将充分过渡到 未来R 01的机制测试，其中eNOS上的特定半胱氨酸残基将被突变， 产生转基因突变小鼠用于体内测试。 总之，这项研究和培训计划旨在了解与以下疾病相关的分子机制： 肠缺血后基质细胞介导的肠保护作用与此同时， 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 一个高度创新的，支持性的平台，让这位年轻的外科医生科学家完成他的科学训练， 向干细胞治疗和再生医学领域的独立研究者过渡。

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