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.

该研究者的提案描述了一个为期5年的项目，旨在研究来自 诱导性多能干细胞作为坏死性小肠结肠炎（NEC）的治疗方式。NEC是一个毁灭性的 新生儿群体中经常需要手术切除肠的腔内紧急情况， 使婴儿的肠道长度不足以吸收营养。它发生在大约10%的早产儿中， 死亡率高达40-50%，每年的医疗费用高达13亿美元。一直缺乏 在过去的十年里，NEC的治疗方式取得了进展，细胞疗法可能提供有益的 改善成果。研究人员假设硫化氢（H2S）是一个关键的旁分泌因子， 间充质干细胞介导的坏死性小肠结肠炎肠保护作用为了更容易地研究 硫化氢的影响，他们建议开发一种近红外H2S特异性探针， 准确定量生物系统中的H2S。进一步提出的研究过度表达硫化氢产生 本发明的目的在于鉴定iPSC衍生的MSC中的酶，并且旨在鉴定分泌的多硫化物，其可能充当细胞内的多硫化物。 信号分子最后，他们评估了Cys 440在eNOS中的作用，Cys 440是一个关键的残基，与eNOS相互作用。 硫化氢促进肠系膜血管舒张和改善实验性NEC的临床结果。的 研究人员提出了三个具体目标：1）确定MSC的硫化氢信号传导在 2）开发和验证硫化氢探针以有效地测量NEC中的H2S， 3）为了评估iPSC衍生的MSC、H2S和一氧化氮（NO）在细胞内的相互作用， 实验性NEC期间肠系膜内皮。 研究者是一名儿科外科科学家，作为K 08获奖者通过NIDDK正式资助。 该资助已于二零二二年五月到期。他现在正在寻找他的第一个R 01奖作为一个早期阶段的调查员。 他的职业目标是利用R 01进一步开发细胞疗法，作为治疗坏死性胰腺炎的可行疗法。 肠炎Markel博士与Notre的Ken Olson博士有着长期的合作和导师关系 Dame/IU Southbend。他是硫化氢信号的国际专家，并将继续协助博士。 Markel与设计用于进一步定量分泌的多硫化物池的测定。马克尔博士还与 本·加斯顿博士是一氧化氮信号的专家，他在当地的研究机构工作，还有蒂姆·莱斯昆博士， 普渡大学的一位大型动物兽医，他曾协助建立了一个NEC的仔猪模型， 马克尔的实验室 总之，本研究旨在了解iPSC衍生的MSC用于提供 保护NEC。该提案极具创新性，调查人员得到了适当的支持， 合作和基础设施到位，以开展研究。本研究的结果将用于提供 随后可以进行人体临床试验之前的最终临床前数据。