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.
Neurodegenerative disorders are mostly incurable conditions with far-reaching social and economic impact. Using animal models of a particular childhood neurodegenerative disorder as well as patient-derived neural progenitor-like cells, this work proposes to identify novel mechanisms that lead to neurodegeneration. Thus, results will be relevant to better understand the disease mechanisms, and advance in treatment and management therapies to reduce the burden of neurodegenerative diseases.