Sulfur Based Stem Cell Therapeutics in Necrotizing Enterocolitis

硫基干细胞治疗坏死性小肠结肠炎

• 批准号: 10659645
• 负责人: TROY A MARKEL
• 金额: $ 42.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659645
• 关键词: Abdomen; Angiogenesis Modulating Agents; Animals; Apoptosis; Award; Biological Assay; Blood flow; Cell Culture System; Cell Proliferation; Cell Therapy; Cells; Cessation of life; Childhood; Clinical; Clinical Trials; Collaborations; Data; Degenerative polyarthritis; Detection; Development; Diabetic Foot Ulcer; Emergency Situation; Endothelium; Enzyme Precursors; Enzymes; Equilibrium; Esters; Evaluation; Excision; Exhibits; Funding; Gases; Generations; Genetic; Goals; Grant; Gut Mucosa; Harvest; Human; Hydrogen Sulfide; Hypoxia; Immune; In Situ; In Vitro; Infant; Inflammatory Response; Infrastructure; Infusion procedures; Institution; International; Intestines; Intra-abdominal; Ischemia; Laboratories; Length; Measures; Mediating; Mediator; Medical; Medical Care Costs; Mentors; Mesenchymal Stem Cells; Mesentery; Methods; Modality; Modeling; Mus; Mutation; Myography; NOS3 gene; National Institute of Diabetes and Digestive and Kidney Diseases; Necrosis; Necrotizing Enterocolitis; Neonatal; Nitric Oxide; Operative Surgical Procedures; Outcome; Patients; Phase; Population; Premature Infant; Production; Property; Quality Control; Recovery; Research; Research Personnel; Role; Safety; Scientist; Sepsis; Signal Transduction; Signaling Molecule; Source; Stress; Sulfur; Surgeon; System; Testing; Therapeutic Effect; Tissues; Transgenic Mice; Transplantation; Tyrosine; Universities; Vasodilation; Veterinarians; Volatilization; absorption; biological systems; career; cell motility; cost; critical limb Ischemia; design; detection method; experimental study; graft vs host disease; gut microbiome; immunogenicity; improved; in vivo; in vivo Model; induced pluripotent stem cell; innovation; intestinal injury; minimally invasive; mortality; nanomolar; novel; nutrition; overexpression; paracrine; polysulfide; porcine model; pre-clinical; premature; pressure; stem cell therapy; stem cells; systemic inflammatory response; therapeutically effective

This investigator's proposal describes a 5-year project designed to study mesenchymal stem cells derived from inducible pluripotent stem cells as a treatment modality for necrotizing enterocolitis (NEC). NEC is a devastating intrabdominal emergency in the neonatal population that often requires the surgical resection of intestine, thereby leaving infants with a suboptimal length of bowel to absorb nutrition. It occurs in roughly 10% of preterm infants, carries a 40-50% mortality rate, and costs $1.3 billion in medical costs annual. There has been lack of advancement in treatment modalities over the last decade for NEC, and cellular therapy may provide beneficial improvements in outcomes. Investigators hypothesize that hydrogen sulfide (H2S) is a key paracrine factor in mesenchymal stem cell mediated intestinal protection during necrotizing enterocolitis. To more readily study the effects of hydrogen sulfide, they propose the development of a near infrared H2S specific probe to more accurately quantify H2S in biological systems. Further proposed studies overexpress hydrogen sulfide producing enzymes in iPSC derived MSCs and aim to identify the secreted polysulfides which likely serve as intracellular signaling molecules. Finally, they assess the role of Cys440 on eNOS as a critical residue that interacts with hydrogen sulfide to promote mesenteric vasodilation and improved clinical outcomes in experimental NEC. The investigators propose three Specific Aims: 1) To define the role of hydrogen sulfide signaling from MSCs during cellular therapy for NEC, 2) To develop and validate a hydrogen sulfide probe to effectively measure H2S in biological systems, and 3) To evaluate the interaction of iPSC derived MSCs, H2S, and Nitric Oxide (NO) on the mesenteric endothelium during experimental NEC. The investigator is a pediatric surgeon scientist who was formally funded through the NIDDK as a K08 awardee. This grant support expired in May 2022. He is now seeking out his first R01 award as an Early Stage Investigator. His career goals are to use this R01 to further develop cellular therapy as a viable treatment for necrotizing enterocolitis. Dr. Markel has a long standing collaborative and mentor relationship with Dr. Ken Olson at Notre Dame/IU Southbend. He is an international expert in hydrogen sulfide signaling and will continue to assist Dr. Markel with assays designed to further quantify the secreted polysulfide pool. Dr. Markel has also collaborated with Dr Ben Gaston at his local institution who is an expert on nitric oxide signaling, as well as Dr. Tim Lescun, a large animal veterinarian at Purdue University, who has assisted in establishing a piglet model of NEC in Dr. Markel's laboratory. In summary, this research aims to understand the mechanism that iPSC derived MSCs use to provide protection in NEC. The proposal is highly innovative and the investigator has the appropriate support, collaborations, and infrastructure in place to carry out the study. Results of this study will be used to provide final preclinical data before human clinical trials can ensue.

该研究人员的提案描述了一个为期 5 年的项目，旨在研究源自以下来源的间充质干细胞： 诱导多能干细胞作为坏死性小肠结肠炎（NEC）的治疗方式。 NEC是毁灭性的 新生儿腹内急症通常需要手术切除肠道，从而 导致婴儿的肠道长度不够理想，无法吸收营养。大约 10% 的早产儿会出现这种情况， 死亡率为 40-50%，每年的医疗费用为 13 亿美元。一直缺乏 过去十年中 NEC 治疗方式取得了进展，细胞疗法可能会带来有益的效果 结果的改善。研究人员假设硫化氢 (H2S) 是一种关键的旁分泌因子 间充质干细胞在坏死性小肠结肠炎期间介导肠道保护。为了更方便地学习 为了研究硫化氢的影响，他们建议开发近红外 H2S 特异性探针，以更多地了解硫化氢的影响。 准确量化生物系统中的 H2S。进一步提出的研究过度表达硫化氢产生 iPSC 衍生的 MSC 中的酶，旨在鉴定可能作为细胞内物质的分泌多硫化物 信号分子。最后，他们评估了 Cys440 作为与 eNOS 相互作用的关键残基的作用。 硫化氢促进肠系膜血管舒张并改善实验性 NEC 的临床结果。这 研究人员提出了三个具体目标：1）确定 MSC 中硫化氢信号传导的作用 NEC 的细胞疗法，2) 开发并验证硫化氢探针，以有效测量 H2S 3) 评估 iPSC 衍生的 MSC、H2S 和一氧化氮 (NO) 对生物系统的相互作用 实验性 NEC 期间的肠系膜内皮。 研究者是一名儿科外科医生科学家，作为 K08 获奖者获得 NIDDK 的正式资助。 这项资助于 2022 年 5 月到期。他现在正在寻求作为早期研究员的第一个 R01 奖项。 他的职业目标是利用 R01 进一步开发细胞疗法，作为坏死性坏死的可行治疗方法。 小肠结肠炎。 Markel 博士与 Notre 的 Ken Olson 博士有着长期的合作和导师关系 女爵士/IU南本德。他是硫化氢信号传导方面的国际专家，将继续协助 Dr. Markel 进行了旨在进一步量化分泌的多硫化物池的检测。马克尔博士也合作过 与当地机构的一氧化氮信号专家 Ben Gaston 博士以及 Tim Lescun 博士一起， 普渡大学大动物兽医，曾协助Dr.建立NEC仔猪模型。 马克尔的实验室。 总之，本研究旨在了解 iPSC 衍生的 MSC 用来提供 NEC 中的保护。该提案具有高度创新性并且研究者得到了适当的支持， 合作以及开展研究的基础设施。这项研究的结果将用于提供 在进行人体临床试验之前获得最终临床前数据。