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.

该研究者的提议描述了一个为期5年的项目，旨在研究源自的间充质干细胞 可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 新生儿种群中的腹部紧急情况通常需要进行手术切除，从而 留下肠道长度下的婴儿，以吸收营养。它发生在大约10％的早产儿中， 携带40-50％的死亡率，每年的医疗费用为13亿美元。缺乏 在过去十年中，NEC的治疗方式进步，细胞疗法可能会提供有益的 结果的改善。研究人员假设硫化氢（H2S）是关键的旁分泌因子 在坏死性小肠结肠炎期间，间充质干细胞介导的肠道保护。更容易研究 硫化氢的影响，他们提出了近红外H2S特异性探针的发展 准确量化生物系统中的H2。进一步提出的研究过表达硫化氢产生 IPSC衍生的MSC中的酶，旨在识别可能用作细胞内的分泌多硫化物 信号分子。最后，他们评估Cys440对ENOS的作用，作为与之相互作用的关键残基 硫化氢可促进肠系膜血管舒张并改善实验NEC的临床结果。这 研究人员提出了三个具体目的：1）定义在MSC中定义硫化氢信号的作用 NEC的细胞治疗，2）开发和验证硫化氢探针以有效测量H2S 生物系统和3）评估IPSC衍生的MSC，H2S和一氧化氮（NO）的相互作用 实验NEC期间的肠系膜内皮。 研究人员是一位小儿外科医生科学家，由NIDDK正式资助为K08获奖者。 这项赠款支持于2022年5月到期。他现在正在寻求他作为早期调查员的第一个R01奖。 他的职业目标是利用此R01进一步发展蜂窝疗法作为坏死的可行疗法 小肠结肠炎。马克尔博士与巴黎圣母院的肯·奥尔森博士建立了长期的合作和导师关系 Dame/IU Southbend。他是硫化氢信号传导的国际专家，并将继续协助博士。 Markel的测定方法旨在进一步量化分泌的多硫化物池。马克尔博士也合作了 与本地机构的本·加斯顿（Ben Gaston）博士是一氧化氮信号的专家，以及蒂姆·莱斯康（Tim Lescun）博士， 普渡大学的一名大型动物兽医，他协助建立了NEC的小猪模型 马克尔的实验室。 总而言之，这项研究旨在了解IPSC得出的MSC提供的机制 NEC的保护。该提案具有很高的创新性，调查员有适当的支持， 合作和基础设施进行了研究。这项研究的结果将用于提供 在人类临床试验之前可以进行最终临床前数据。