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

 描述（由申请人提供）：这个K99/R 00职业发展奖提案描述了一个为期两年的指导和三年的独立研究计划，对于主要研究者作为独立研究者的发展至关重要。主要研究者在西班牙巴塞罗那大学获得博士学位，因为她在Marian Martinez Balbas博士的监督下了解了神经管发育中涉及的染色质调控机制。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，在大脑发育和疾病的遗传学以及在使用多能干细胞模拟神经系统疾病的培训。为了获得神经系统疾病小鼠模型的生成和使用经验，她正在过渡到Ulrich Mueller博士的实验室。此外，为了帮助特定的技术，帮助确定工作机会，准备工作面试，并建立一个实验室，由我的导师组成的顾问团队的建议，以及Alysson Muotri博士和Stephanie Cherqui博士，两位年轻的研究人员都拥有关于如何管理实验室的最新知识，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，以实现她的目标，成为一个成功的独立调查员。这项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）一个可能无处不在的刺激如何影响特定的神经元群体，2）抗性神经元如何对抗毒性或3）如何取代失去的神经元群体。为了实现这一目标，她将特别关注一个特定的围产期发病的神经退行性疾病，在腺苷单磷酸脱氨酶2（AMPD 2）基因突变引起的，她最近确定。AMPD 2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。该研究计划旨在验证AMPD 2以时间和空间依赖性方式调节特定神经元发育和存活的中心假设。该假设建立在AMPD 2缺陷个体中观察到的临床特征以及从患者来源的神经祖细胞样细胞和该疾病的鼠模型获得的初步数据上。拟议的研究将分析AMPD 2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。这些将使用结合人类多能干细胞和该疾病的小鼠模型的实验策略进行测试。这些结果将为支持主要研究者的研究目标提供坚实的基础，这些目标有望提供1）更好地理解导致神经退行性变的机制，2）深入了解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.