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

探索 AMP 脱氨酶在神经元发育和变性中的作用。

基本信息

批准号：
9441065
负责人：
Naiara Aquizu Lopez
金额：
$ 24.89万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9441065
关键词：
Adenosine Monophosphate Advisory Committees Affect Age Alzheimer&apos s Disease Animal Model Axon Biomedical Research Brain Brain Death Brain Stem Brain region California Cell model Cells Cerebellum Childhood Chromatin Clinical Complement Congenital cerebellar hypoplasia Corpus Callosum DNA biosynthesis Data Deaminase Deamination Defect Development Disease Disease model Doctor of Philosophy Energy-Generating Resources Engraftment Enzymes Etiology Foundations Generations Genes Genetic Goals Guanine Nucleotides Guanosine Triphosphate Human Impairment In Vitro Incidence Individual Interview K-Series Research Career Programs Knockout Mice Knowledge Laboratories Lead Maintenance Mediating Mentors Metabolic Mus Mutation Nerve Degeneration Nervous System Physiology Neural Tube Development Neurodegenerative Disorders Neurologic Neurological Models Neurons Occupations Parkinson Disease Pathogenesis Patients Perinatal Phase Pluripotent Stem Cells Population Principal Investigator Process Prosencephalon Protein Biosynthesis Protein Isoforms Protein Synthesis Inhibition Proteins Purine Nucleotides RNA chemical synthesis Replacement Therapy Research Research Personnel Resistance Role Severities Social Impacts Solid Spain Specificity Stimulus Structure Suggestion Supervision Survival Rate Techniques Testing Time Toxic effect Training Training Programs Translations Universities Vertebrates Vulnerable Populations Weight Work brain malformation brain morphology economic impact experience experimental study human pluripotent stem cell in vivo insight malformation meetings mouse model nerve stem cell nervous system disorder neurogenesis neuron development neuron loss neuronal survival novel nucleotide metabolism null mutation paralogous gene postnatal programs public health relevance spatiotemporal treatment strategy

项目摘要

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.

描述（由应用程序提供）：该K99/R00职业发展奖提案描述了一项为期两年且为期三年的独立研究计划，这对于主要研究人员作为独立研究者的发展至关重要。首席研究人员在西班牙巴塞罗那大学获得了博士学位，因为她在玛丽安·马丁内斯·巴尔巴斯（Marian Martinez Balbas）的监督下，了解了染色质调节机制。然后，她搬到了加利福尼亚大学圣地亚哥分校，在那里她加入了约瑟夫·格里森（Joseph Gleeson）博士的实验室，培训脑发育和疾病的遗传学以及使用多能干细胞来建模神经系统疾病。为了获得在神经系统疾病的产生和使用小鼠模型的经验，她正在过渡到乌尔里希·穆勒（Ulrich Mueller）博士的实验室。此外，为了帮助采用特定技术，帮助确定工作机会，准备工作面试并建立实验室，由我的导师组成的咨询小组的建议，以及Alysson Muotri博士和Stephanie Cherqui博士和Stephanie Cherqui博士，都是年轻的调查员，他们都是最新的有关如何管理实验室的知识的年轻调查员，将是无价的。最后，拟议的课程，科学会议和下水道将完成她的培训计划，以实现成为成功的独立调查员的目标。拟议工作的长期研究目标是寻求答案，以挑战神经退行性疾病的基础问题，即1）可能无处不在的刺激如何影响特定的神经元种群，2）耐药性神经元如何抵消毒性或3）如何替代丢失的神经元种群。为了实现这一目标，她将特别关注特定的围产期发作神经退行性疾病，该神经退行性疾病是由她最近确定的腺苷单磷酸脱氨酶2（AMPD2）基因引起的。 AMPD2是嘌呤核丁基代谢中鸟嘌呤核丁基合成（例如GTP）的关键酶，但是对其神经功能的知识知之甚少。研究计划的建议是测试AMPD2以时间和空间依赖性方式调节特定神经元发展和生存的中心假设。该假设建立在AMPD2缺乏个体中观察到的临床特征，以及从患者衍生的神经元基因（如细胞）和疾病的鼠模型中获得的初步数据。拟议的研究将分析AMPD2缺乏症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。这些将使用实验策略进行测试，该策略结合了人类多能干细胞和疾病的鼠模型。结果将为支持主要研究人员的研究目标提供坚实的基础，该目标有望提供1）更好地理解导致神经变性的机制，以及2）对治疗和替代疗法的策略的见解。