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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.