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.

Public Health Relevance

NO has a proven role in the pathogenesis of common diseases as hypertension, diabetes, asthma etc. The impact of argininine substrate availability in the cell on NO synthesis is unknown. Our work combines mouse models, state of the art infusion strategies and human urea cycle patients to understand this contribution in renal disease. Moreover, this work may identify a novel target for regulation and manipulation of NO.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK081735-04
Application #
8259808
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2009-07-01
Project End
2012-08-31
Budget Start
2012-05-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$58,145
Indirect Cost
$4,307
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Erez, Ayelet (2013) Argininosuccinic aciduria: from a monogenic to a complex disorder. Genet Med 15:251-7
Nagamani, Sandesh C S; Erez, Ayelet; Ben-Zeev, Bruria et al. (2013) Detection of copy-number variation in AUTS2 gene by targeted exonic array CGH in patients with developmental delay and autistic spectrum disorders. Eur J Hum Genet 21:343-6
Nagamani, Sandesh C S; Erez, Ayelet; Lee, Brendan (2012) Argininosuccinate lyase deficiency. Genet Med 14:501-7
Nagamani, Sandesh C Sreenath; Erez, Ayelet; Bay, Carolyn et al. (2012) Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44. Eur J Hum Genet 20:176-9
Nagamani, Sandesh C S; Campeau, Philippe M; Shchelochkov, Oleg A et al. (2012) Nitric-oxide supplementation for treatment of long-term complications in argininosuccinic aciduria. Am J Hum Genet 90:836-46
Erez, Ayelet; Shchelochkov, Oleg A; Plon, Sharon E et al. (2011) Insights into the pathogenesis and treatment of cancer from inborn errors of metabolism. Am J Hum Genet 88:402-21
Brunetti-Pierri, Nicola; Lanpher, Brendan; Erez, Ayelet et al. (2011) Phenylbutyrate therapy for maple syrup urine disease. Hum Mol Genet 20:631-40
Nagamani, Sandesh C Sreenath; Erez, Ayelet; Bader, Patricia et al. (2011) Phenotypic manifestations of copy number variation in chromosome 16p13.11. Eur J Hum Genet 19:280-6
Liu, Pengfei; Erez, Ayelet; Nagamani, Sandesh C Sreenath et al. (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:889-903
Erez, Ayelet; Nagamani, Sandesh C S; Shchelochkov, Oleg A et al. (2011) Requirement of argininosuccinate lyase for systemic nitric oxide production. Nat Med 17:1619-26

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