The purpose of this grant is to seek financial support for mentoring activities in patient -oriented research to allow young trainees to experience the excitement of scientific discovery. By mentoring, this applicant hopes to build the next generation of clinician investigators by having them experience the wonderful rewards of taking new biologic and health knowledge they have discovered and translating that knowledge into tangible benefits for patients, such as better diagnostic strategies or novel clinical therapies. In order to support such training efforts, this grant would provide financial resources for the applicant, so that she could maintain her own research program while freeing up time for mentoring activities. These mentoring activities involve teaching trainees how to build hypotheses, design protocols, achieve the highest standards of patient safety, address regulatory issues, develop manuscripts, write grants, and meet their career goals. The trainees will work within the applicant's research program in reproductive genetics and physiology. The applicant discovered that mutations in the kisspeptin-GPR54 signaling pathway result in an absence of pubertal development and hypogonadotropic hypogonadism across mammalian species. She is now using kisspeptin administration as the first direct probe of GnRH neuronal integrity in human reproductive biology. Study protocols will include healthy volunteers and patients with congenital GnRH deficiencies who have already been extensively phenotyped and genotyped. Kisspeptin (or analogous compounds) may provide another avenue for therapeutic intervention for patients with reproductive cancers, endometriosis, infertility, and abnormalities of pubertal timing. Patients with reproductive cancers may derive additional benefits given the metastasis suppressor properties of this pathway. Taken together, these projects and the applicant's mentoring will provide a strong program for training new clinical investigators in patient-oriented research.

Public Health Relevance

This grant will support the mentoring activities of the applicant in reproductive physiology so that she can train beginning clinical investigators to have passion for patient oriented research and to develop the skills to build their own investigative programs.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Pediatrics Subcommittee (CHHD)
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Lamar, Charisee A
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Massachusetts General Hospital
United States
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Seminara, Stephanie B (2014) Fatness and fertility: which direction? J Clin Invest 124:2853-4
Calder, Michele; Chan, Yee-Ming; Raj, Renju et al. (2014) Implantation failure in female Kiss1-/- mice is independent of their hypogonadic state and can be partially rescued by leukemia inhibitory factor. Endocrinology 155:3065-78
Sidhoum, Valerie F; Chan, Yee-Ming; Lippincott, Margaret F et al. (2014) Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab 99:861-70
Shi, Chang-He; Schisler, Jonathan C; Rubel, Carrie E et al. (2014) Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 23:1013-24
Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W et al. (2013) Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab 98:E943-53
Lippincott, Margaret F; True, Cadence; Seminara, Stephanie B (2013) Use of genetic models of idiopathic hypogonadotrophic hypogonadism in mice and men to understand the mechanisms of disease. Exp Physiol 98:1522-7
Miraoui, Hichem; Dwyer, Andrew A; Sykiotis, Gerasimos P et al. (2013) Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am J Hum Genet 92:725-43
Margolin, David H; Kousi, Maria; Chan, Yee-Ming et al. (2013) Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. N Engl J Med 368:1992-2003
Liu, Zhongfa; Ren, Chen; Jones, William et al. (2013) LC-MS/MS quantification of a neuropeptide fragment kisspeptin-10 (NSC 741805) and characterization of its decomposition product and pharmacokinetics in rats. J Chromatogr B Analyt Technol Biomed Life Sci 926:1-8
Silveira, Leticia Gontijo; Latronico, Ana Claudia; Seminara, Stephanie Beth (2013) Kisspeptin and clinical disorders. Adv Exp Med Biol 784:187-99