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.

项目概要 这项新的研究者提案描述了一项为期 4 年的外科医生科学家发展培训计划 这位新研究员的工作重点是干细胞生物学和干细胞。 他目前是该大学的外科助理教授。 IUSOM 的职业目标是利用这个 K08 奖项来支持他发展为高技能人才的承诺。 科学家，并从长远来看转变为一名成功的、独立的、由 NIH 资助的外科医生科学家。 IUSOM 还保证申请人有 75% 的受保护时间投入研究工作。 时间承诺，该机构为申请人提供了充足的启动包，其中包括 实验室空间、研究经费和5年的辅助支持是职业发展计划的基石。 是一个模范的科学顾问委员会，五位科学家来自不同的背景，而且每一位都是。 他们被认为是各自领域的国际权威，在支持年轻科学家方面有着悠久的记录。 并与委员会密切协商，提供有效的指导。 教育计划，包括额外的课程、每周实验室会议、全国会议和 组织研究计划来完成他的培训。 该提案研究了与间充质基质细胞介导的相关的潜在机制 申请人提出了一种新的假设，提出： 终末器官肠道保护是由基质细胞释放硫化氢气体介导的，其作用 通过传出途径，如 eNOS，促进改善肠系膜灌注。 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。 目标 2 然后尝试阐明旁分泌介质在肠道 I/R 后促进宿主保护的作用。 硫化氢利用肠系膜内皮促进改善的下游机制 缺血后的灌注{该提案研究了一氧化氮作为这种机制，并着眼于 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 这些数据将作为微血管内白细胞捕获的充分转变。 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 生成用于体内测试的转基因突变小鼠。} 总之，本研究和培训计划旨在了解与相关的分子机制 肠道缺血后基质细胞介导的肠道保护。 经验丰富的专家指导小组以及 IUSOM 的强大机构支持将提供 为这位年轻的外科医生科学家提供一个高度创新的支持平台，以完成他的科学培训并做出贡献 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

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

实验性坏死性小肠结肠炎期间微生物组变化和粪便挥发性有机化合物的评估。

• 发表时间: 2021-06
• 作者: Hosfield, Brian D;Drucker, Natalie A;Pecoraro, Anthony R;Shelley, William C;Li, Hongge;Baxter, Nielson T;Hawkins, Troy B;Markel, Troy A
• 通讯作者: Markel, Troy A

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

一切都在牛奶中：硫酸软骨素可作为坏死性小肠结肠炎的潜在预防疗法。

• 发表时间: 2021
• 影响因子: 3.6
• 作者: Knowles, Thomas A;Hosfield, Brian D;Pecoraro, Anthony R;Li, Hongge;Shelley, W Christopher;Markel, Troy A
• 通讯作者: Markel, Troy A

Age disparities in intestinal stem cell quantities: a possible explanation for preterm infant susceptibility to necrotizing enterocolitis.

肠道干细胞数量的年龄差异：早产儿易患坏死性小肠结肠炎的可能解释。

• 发表时间: 2022-12
• 影响因子: 1.8
• 作者: Hosfield, Brian D;Shelley, W Christopher;Mesfin, Fikir M;Brokaw, John P;Manohar, Krishna;Liu, Jianyun;Li, Hongge;Pecoraro, Anthony R;Singh, Kanhaiya;Markel, Troy A
• 通讯作者: Markel, Troy A

Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide.

间充质干细胞通过硫化氢和内皮一氧化氮促进肠系膜血管舒张。

• 发表时间: 2019
• 作者: Te Winkel, Jan;John, Quincy E;Hosfield, Brian D;Drucker, Natalie A;Das, Amitava;Olson, Ken R;Markel, Troy A
• 通讯作者: Markel, Troy A

Effects of Manganese Porphyrins on Cellular Sulfur Metabolism.

锰卟啉对细胞硫代谢的影响。

• 发表时间: 2020-02-22
• 作者: Olson, Kenneth R;Gao, Yan;Steiger, Andrea K;Pluth, Michael D;Tessier, Charles R;Markel, Troy A;Boone, David;Stahelin, Robert V;Batinic;Straubg, Karl D
• 通讯作者: Straubg, Karl D