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.

这位研究人员的提案描述了一个为期5年的项目，旨在研究来源于 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是一个毁灭性的 新生儿的腹内急症，通常需要手术切除肠道，因此 使婴儿的肠道长度低于吸收营养的最佳长度。大约10%的早产儿会发生这种情况， 死亡率为40%-50%，每年的医疗费用为13亿美元。一直以来都缺乏 在过去的十年中，NEC的治疗方式和细胞疗法的进展可能会提供有益的 在结果方面有所改善。研究人员假设，硫化氢(H2S)是一种关键的旁分泌因素 间充质干细胞在坏死性小肠结肠炎中的肠道保护作用。为了更容易地研究 对于硫化氢的影响，他们建议开发一种近红外硫化氢专属探头，以获得更多 准确定量生物系统中的硫化氢。进一步研究过度表达硫化氢 IPSC来源的MSCs中的酶，目的是鉴定可能作为细胞内功能的分泌的多硫化物 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对eNOS的作用 硫化氢促进肠系膜血管扩张和改善实验性NEC的临床结果。这个 研究人员提出了三个具体目标：1)确定来自MSCs的硫化氢信号在 NEC的细胞治疗，2)开发和验证硫化氢探针，以有效地测量 生物系统，以及3)评估IPSC来源的MSCs、硫化氢和一氧化氮(NO)对 实验性NEC时肠系膜内皮细胞的变化。 这位研究员是一位儿科外科科学家，他作为K08奖获得者通过NIDDK得到了正式资助。 这项赠款支持已于2022年5月到期。他现在正在寻找他作为早期调查员的第一个R01奖。 他的职业目标是利用这款R01进一步开发细胞疗法，作为一种可行的坏死性治疗方法 小肠结肠炎。马克尔博士与巴黎圣母院的肯·奥尔森博士有着长期的合作和指导关系 圣母院/伊利诺伊州南本德。他是硫化氢信号方面的国际专家，并将继续协助Dr。 Markel和旨在进一步量化分泌的多硫化物池的分析。马克尔博士还与 与他当地机构的一氧化氮信号专家本·加斯顿博士以及蒂姆·莱斯昆博士一起， 他是普渡大学的一位大型动物兽医，曾协助建立了NEC的仔猪模型。 马克尔的实验室。 总之，本研究旨在了解IPSC来源的MSCs用于提供 NEC中的保护。该提案具有很高的创新性，调查员得到了适当的支持， 合作，以及开展这项研究的基础设施。这项研究的结果将用于提供 在人体临床试验之前的最终临床前数据。