Exploring the role of AMP DEAMINASES in neuronal development and degeneration.

 描述(由申请人提供)：这份K99/R00职业发展奖提案描述了一项为期两年的指导和三年的独立研究计划，这对首席调查员作为独立调查员的发展至关重要。这位首席研究员在西班牙巴塞罗那大学获得博士学位，原因是她在玛丽安·马丁内斯·巴尔巴斯博士的指导下了解了涉及神经管发育的染色质调控机制。然后她搬到了加州大学圣地亚哥分校，在那里她加入了约瑟夫·格里森博士的实验室，接受大脑发育和疾病的遗传学方面的培训，以及使用多能干细胞来模拟神经疾病。为了获得建立和使用神经系统疾病小鼠模型的经验，她正在过渡到乌尔里希·米勒博士的实验室。此外，我的导师、艾莉森·穆特里博士和斯蒂芬妮·切尔基博士组成的顾问团队提出的建议，对于帮助掌握特定技术、帮助寻找工作机会、准备求职面试和建立实验室，都将是非常宝贵的。最后，拟议的课程、科学会议和研讨会将补充她的培训计划，以实现她成为一名成功的独立调查员的目标。这项拟议工作的长期研究目标是寻求神经退行性疾病潜在的挑战性问题的答案，例如1)假设无处不在的刺激如何影响特定的神经元群体，2)耐药神经元如何抵消毒性，或3)如何替换丢失的神经元群体。为了实现这一目标，她将特别关注一种特殊的围产期起病神经退行性疾病，这是由她最近发现的腺苷单磷酸脱氨酶2(AMPD2)基因突变引起的。AMPD2是嘌呤核苷酸代谢中鸟嘌呤核苷酸合成(如GTP)的关键酶，但对其神经功能知之甚少。该研究计划建议测试AMPD2以时间和空间依赖的方式调控特定神经元发育和存活的中心假设。这一假说建立在AMPD2缺陷个体的临床特征，以及从患者来源的神经前体细胞和疾病的小鼠模型中获得的初步数据基础上。拟议的研究将分析AMPD2缺乏的神经发育和神经退行性后果，以及提供特定时空脆弱性的机制。这些将使用一种实验策略进行测试，该策略结合了人类多能干细胞和这种疾病的小鼠模型。这些结果将为支持主要研究人员的研究目标提供坚实的基础，这些目标有望1)更好地理解导致神经退化的机制，2)洞察治疗和替代疗法的策略。

 DESCRIPTION (provided by applicant): This K99/R00 career development award proposal describes a two-year mentored and three-year independent research program essential for the development of the principal investigator as an independent investigator. The principal investigator received her PhD at the University of Barcelona, Spain, for the work she performed understanding chromatin regulatory mechanisms involved in neural tube development under the supervision of Dr. Marian Martinez Balbas. She then moved to University of California, San Diego where she joined Dr. Joseph Gleeson's laboratory to train in genetics of brain development and disease as well as in the use of pluripotent stem cells to model neurological disorders. In order to gain experience in the generation and use of mouse models for neurological disorders, she is transitioning to Dr. Ulrich Mueller's laboratory. Furthermore, to assist with specific techniques, help identify job opportunities, prepare for job interviews, and build a laboratory, suggestions from the advisory team formed by my mentors, and Dr. Alysson Muotri and Dr. Stephanie Cherqui, both young investigators with the most current knowledge about how to manage a lab, will be invaluable. Finally, proposed courses, scientific meetings and seminars will complement her training program to accomplish her goal to become a successful independent investigator. The long-term research goal of the proposed work is to seek answers to challenging questions underlying neurodegenerative disorders, as to 1) how a presumably ubiquitous stimulus affects specific neuronal populations, 2) how resistant neurons counteract toxicity or 3) how to replace the lost neuronal population. To achieve this goal she will specifically focus on a particular perinatal onset neurodegenerative disorder, caused by mutations in Adenosine Monophosphate Deaminase 2 (AMPD2) gene that she recently identified. AMPD2 is a key enzyme for guanine nucleotide synthesis (e.g. GTP) in purine nucleotide metabolism, however little is known about its neurological functions. The research plan proposes to test the central hypothesis that AMPD2 regulates specific neuronal development and survival in time- and space-dependent manner. This hypothesis is built upon clinical features observed in AMPD2 deficient individuals, and preliminary data obtained from patient derived neural progenitor like cells and a murine model of the disease. The proposed studies will analyze neurodevelopmental and neurodegenerative consequences of AMPD2 deficiency and the mechanisms that provide specific spatiotemporal vulnerability. These will be tested using an experimental strategy that combines human pluripotent stem cells and murine models of the disorder. The results will provide a solid foundation to support principal investigators' research goals that hold the promise to offer 1) better understanding of mechanisms that lead to neurodegeneration and 2) insights into strategies for treatment and replacement therapies.