Determinants of Neural & Embryonic Stem Cell Potency

描述(由申请人提供)： 这份提案描述了一项为期五年的培训计划，旨在发展整合神经、干细胞和系统生物学的研究专业知识。申请者是医学博士，在计划开始日期之前，他将在哈佛医学院完成病理学住院医师和临床义务的输血医学奖学金。该候选人的临床兴趣是干细胞治疗领域，特别是人体干细胞的分离、培养和操作。他目前正在世界著名的干细胞、细胞重编程和发育生物学专家鲁道夫·雅尼施博士的指导下接受基础科学培训。哈佛大学输血医学项目负责人莱斯利·西尔伯斯坦博士将在拟议的培训期内共同指导申请者，帮助申请者转变为独立研究人员。一个由备受尊敬的医生和基础科学家组成的咨询委员会将提供实验见解和职业指导。申请者致力于科学研究的学术生涯，结合他将在培训期间作为研究人员和临床医生发展的技能。这项拟议研究的目标是分析神经干细胞命运的表观遗传学，并确定参与这一过程的基因。神经干细胞在再生医学领域有着广阔的前景，包括治疗神经退行性疾病和神经损伤。然而，人们对这些细胞的生物学知之甚少。为了最大限度地发挥神经干细胞的临床效果，重要的是确定提供其发展潜力并同时限制其发展潜力的基因组的性质。候选人将结合核移植技术、表达和染色质图谱，以及在小鼠模型系统中对候选基因进行功能测试来解决这个问题。核移植提供了一种全局和公正的方法，将神经干细胞重新编程为多能状态。结合表达和染色质图谱，核移植可以帮助识别候选基因和表观遗传标记，这些基因和表观遗传标记决定了多潜能神经干细胞与多潜能胚胎干细胞的命运。已建立的异位表达和敲除基因功能的遗传工具为测试这些候选效力基因的作用提供了手段。这一系列研究应该为改变干细胞命运以改善遗传和获得性神经病理疾病的方法提供概念性和治疗性的见解。

DESCRIPTION (provided by applicant): This proposal describes a five-year training program aimed at developing research expertise that integrates neural, stem cell and systems biology. The applicant is a MD/PhD who will have completed pathology residency and clinical obligations for a transfusion medicine fellowship at Harvard Medical School prior to the proposed start date. The candidate's clinical interests are in the area of stem cell therapy, especially in the isolation, culturing, and manipulation of human somatic stem cells. He is currently receiving basic science training under the mentorship of Dr. Rudolf Jaenisch, a world-renowned expert on stem cells, cellular reprogramming, and developmental biology. Dr. Leslie Silberstein, head of the Harvard Transfusion Medicine program, will co-mentor the applicant during the proposed training period facilitating applicant's transition into an independent investigator. An advisory committee of highly respected physician and basic scientists will provide experimental insight and career guidance. The applicant is committed to an academic career in scientific research combining the skills he will develop as a researcher and clinician during the training period. The goal of the proposed research is to analyze the epigenetics of the neural stem cell fate and identify genes involved in the process. Neural stem cells hold great promise in the field of regenerative medicine including the treatment of neurodegenerative diseases and neural injury. However, very little is known about the biology of these cells. To maximize the clinical effectiveness of neural stem cells, it will be important to determine the nature of the genome that provides and at the same time limits their developmental potential. The candidate will use a combination of nuclear transfer techniques, expression and chromatin profiling, and functional testing of candidate genes in the mouse model system to address this problem. Nuclear transfer provides a global and unbiased method to reprogram the neural stem cell to a pluripotent state. Combined with expression and chromatin profiling, nuclear transfer can help identify candidate genes and epigenetic marks that determine the multipotent neural versus the pluripotent embryonic stem cell fate. Established genetic tools for ectopically expressing and knocking down gene function provide means to test the role of these candidate potency genes. This line of research should provide conceptual and therapeutic insight into means for altering stem cell fates for the amelioration of genetic and acquired neuropathologic disease.