Metabolite channeling in the urea cycle and production of nitric oxide

该建议书描述了一项为期5年的有指导的培训经验，旨在引导您在 学术医学。申请人拥有医学博士学位和博士学位，具有分子研究经验。 生物学、生物化学和细胞生物学；她目前正在完成临床遗传学奖学金。这个 贝勒医学院的环境在各个方面提供了独特的优势组合 医学遗传学(临床护理、诊断实验室和研究)以及基础科学研究。这个 实验室导师是尿素循环紊乱(UCD)领域的世界知名领导者，其成员 咨询委员会是经过精心挑选的，以提供拟议中的 研究项目以及为医生-科学家申请者提供职业指导。该项目 结合小鼠遗传学、代谢流量研究和人类临床研究，剖析 内源，尿素循环衍生的精氨酸通量到一氧化氮(NO)的产生。我们将研究精氨酸和 NO在健康和特定疾病中的产生，在这些疾病中，NO在发病机制中具有已证实的作用，使用两者 小鼠模型和人类病人。该项目的具体目标包括生成和表征一个 一种新的条件性基因敲除小鼠模型，在该模型中，内源性、细胞内精氨酸的产生 肾脏受损。这一结果将与出现高精氨酸血症和 精氨酸缺乏症。尿素循环障碍是酶的缺陷，可以提供洞察如何 精氨酸的可获得性可能影响全身NO的产生。通过理解这一点，我们或许能够 合理设计药物治疗糖尿病、肾功能衰竭、 和心血管疾病。虽然这些治疗方法中的许多仍然是推测的，但更好的 了解调节这一功能的潜在机制最终将提高我们的能力 实施这样的疗法。这项建议将为申请人提供两项新技术方面的培训 人类和小鼠遗传学，以及动态稳定同位素测量。这段时间的辅导培训 科学的设计、实施和沟通将补充申请者的持续发展 作为一名临床医生，最终导致了独立的研究计划和长期的学术生涯 医药。

The proposal describes a 5 year mentored training experience designed to lead to an independent career in academic medicine. The applicant holds both MD and PhD degrees with research experience in molecular biology, biochemistry and cell biology; she is currently completing a clinical genetics fellowship. The environment at Baylor College of Medicine provides a unique combination of strengths in a variety of aspects of medical genetics (clinical care, diagnostic labs, and research) as well as basic science research. The laboratory mentor is a world renowned leader in the field of urea cycle disorders (UCD) and the members of the advisory committee have been carefully selected to provide expertise in several aspects of the proposed research project as well as provide career guidance for the physician-scientist applicant. The project combines mouse genetics, metabolic flux studies, and human clinical research to dissect the contribution of endogenous, urea cycle-derived Arginine flux to Nitric Oxide (NO) production. We will study Arginine and NO production in health and in specific diseases where NO has a proven role in the pathogenesis using both mouse models and human patients. The specific aims of this project include generating and characterizing a novel conditional knockout mouse model in which endogenous, intracellular Arginine production by the kidney is impaired. The results will be compared to human patients presenting with hyperargininemia and Arginine deficiency. Urea cycle disorders are enzymatic deficiencies that can provide insight into how Arginine availability may affect whole body NO production. By understanding this, we may be able to rationally devise pharmacological treatment for NO dysregulation in diseases such as diabetes, renal failure, and cardiovascular disease. While many of these therapeutic approaches remain speculative, better understanding of the underlying mechanisms that regulate the function will ultimately improve our ability to implement such therapies. This proposal will provide the applicant with training in new technologies in both human and mouse genetics, and dynamic stable isotope measurements. This period of mentored training in scientific design, implementation and communication will complement the applicant's continued development as a clinician, eventually resulting in an independent research program and a long-term career in academic medicine.