Characterization of the macrophage-derived regenerative signals in intestine

肠道中巨噬细胞衍生的再生信号的表征

基本信息

批准号：
9146344
负责人：
Subhrajit Saha
金额：
$ 15.53万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9146344
关键词：
Abdomen Animals Autologous Biology Blood Cells Bone Marrow Bone Marrow Transplantation Cell Survival Cell Therapy Cells Cessation of life Collaborations Conditioned Culture Media Development Plans Developmental Biology Dichloromethylene Diphosphonate Digestive System Disorders Educational process of instructing Endothelial Cells Environment Epithelial Epithelial Cells Family member Genetic Transcription Genetically Engineered Mouse Goals Growth Health Home environment Homeostasis Human ITGAM gene In Vitro Individual Inflammatory Injury Intestinal Secretions Intestines Intravenous Knockout Mice Laboratories Leadership Learning Ligands Liver diseases Medicine Mentors Mesenchymal Modeling Molecular Biology Mus Myeloid Cells Myofibroblast Natural regeneration Nature Normal tissue morphology Organoids Pathway interactions Phenotype Play Porcupines Process Proliferating Proteins Radiation Radiation Injuries Radiation Oncology Radiation Toxicity Radiation therapy Radiobiology Regenerative Medicine Reporting Research Research Personnel Research Project Grants Role Signal Pathway Signal Transduction Small Intestines Stem Cell Research Stem cells Stromal Cells Survival Analysis Syndrome TLR9 gene Testing Therapeutic Tissues Training Transgenic Mice Transplantation Universities Whole-Body Irradiation Wnt proteins base beta catenin career development chemokine receptor college design experience falls gastrointestinal improved in vivo injured injury and repair intestinal crypt intestinal homeostasis irradiation macrophage monocyte mortality mouse model preconditioning professor regenerative regenerative therapy repaired research study skills small hairpin RNA stem cell biology stem cell niche stromal progenitor

项目摘要

DESCRIPTION (provided by applicant): The candidate is Assistant Professor with considerable experience in studies of regenerative medicine and radiation biology. However, in order for the applicant to transition into a fully independent investigator, an additional supervisd training period is imperative. Dr. Guha who has mentored Dr. Saha on radiation induced normal tissue injury such as intestine will serve as mentor for current proposal. Dr. Jefferey Pollard has extensive research experience in the study of macrophage biology along with Dr. Timothy Wang pioneered in intestinal stem cell research will serve as an ideal co-mentors for this additional training. The research project will be primarily carried out in the department of Radiation Oncology and some part in developmental and molecular biology at the Albert Einstein College of Medicine which offers a scientifically motivating, collaborative and inspiring environment. Intestinal stem cell based research will be held in Dr. Wang's laboratory in Division of Digestive and Liver disease, Columbia University. The proposed five year career development plan is focused on: i) conferring upon the candidate a strong background in radiation injury, regenerative therapeutics and intestinal stem cell biology, ii) improving his research skills and fundamentals as well as the learning of new experimental approaches, iii) facilitating productive collaborations with established researchers and iv) developing his teaching, training, and group leadership skills. The main goal of the current research project is to characterize the macrophage derived Wnt ligands as regenerative signals by which macrophage regulates the intestinal homeostasis and induce the regeneration/repair process following intestinal injury. To test this hypothesis Dr. Saha proposed to use genetically engineered mice model to elucidate the role of macrophage derived Wnt to mitigate radiation induced intestinal injury. The studies are divided into three specific aims: 1.The identification of macrophages derived Wnt in intestinal regeneration following radiation injury. 2. The elucidation of the role chemokine receptor CCR2 in recruitment of circulating monocyte in irradiated intestine and mitigation of radiation injury. 3. Adoptive cell therapy with ex-vivo modulated autologous macrophage to induce Wnt secretion for intestinal injury.

描述（由申请人提供）：候选人是助理教授，在再生医学和放射生物学研究方面拥有丰富的经验。然而，为了使申请人转变为完全独立的研究者，额外的监督培训期是必要的。 Guha 博士曾指导 Saha 博士研究辐射引起的正常组织损伤（如肠道），他将担任当前提案的导师。杰弗里·波拉德博士 Timothy Wang 博士在巨噬细胞生物学研究方面拥有丰富的研究经验，并且在肠道干细胞研究方面开创了先河，将成为本次额外培训的理想共同导师。该研究项目将主要在阿尔伯特·爱因斯坦医学院的放射肿瘤学系以及发育和分子生物学系进行，该系提供了一个科学激励、协作和鼓舞人心的环境。基于肠道干细胞的研究将在哥伦比亚大学消化和肝脏疾病系王博士的实验室进行。拟议的五年职业发展计划侧重于：i）赋予候选人在辐射损伤、再生治疗和肠道干细胞生物学方面的强大背景，ii）提高他的研究技能和基础知识以及新实验方法的学习， iii) 促进与知名研究人员的富有成效的合作，以及 iv) 发展他的教学、培训和团队领导技能。当前研究项目的主要目标是将巨噬细胞衍生的 Wnt 配体表征为再生信号，巨噬细胞通过该信号调节肠道稳态并诱导肠道损伤后的再生/修复过程。为了验证这一假设，Saha 博士建议使用基因工程小鼠模型来阐明巨噬细胞衍生的 Wnt 在减轻辐射引起的肠道损伤中的作用。这些研究分为三个具体目标： 1.鉴定源自Wnt的巨噬细胞在辐射损伤后肠道再生中的作用。 2.阐明趋化因子受体CCR2在受辐射肠道募集循环单核细胞和减轻辐射损伤中的作用。 3.使用离体调节的自体巨噬细胞诱导Wnt分泌以治疗肠道损伤的过继细胞疗法。