A unique neural network within the hypothalamus initiates and maintains reproductive function in humans. It accomplishes this task by coordinating the synthesis and pulsatile secretion of a single neuroendocrine decapeptide, gonadotropin-releasing hormone (GnRH), from this neural network. In the last two decades, several genes and pathways that govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. Several G protein-coupled receptors (GPCRs) and their cognate ligands have been implicated in the neuroendocrine control of human reproduction. However, the knowledge about many of these new genes and pathways are still in the early stages and require further investigation. The overall goal of my research project is to explore the role of th prokineticin system in the neural network that controls human reproductive development and function. The prokineticin signaling system, prokineticin 2 (PROK2) and PROK2 receptor (PROKR2), has recently emerged as a critical regulator of the neuroendocrine control of reproduction in both mice and humans. PROK2 and PROKR2 are highly expressed in the central nervous system and play an important role in olfactory bulb neurogenesis and subsequently in GnRH neuronal migration. Prokineticin 2 also acts as a key circadian output molecule from the suprachiasmatic nucleus and regulates ingestive behavior in animals. Although both human and mouse studies have confirmed and firmly established a key role of the prokineticin pathway in mammalian reproduction, several features of this biology remain puzzling, suggesting a more complex systems biology of this pathway in humans. The objective of this proposal is to clarify the genetic architecture of GnRH deficiency and to investigate the molecular mechanisms through which PROKR2 mutations affect receptor function.
My first aim i s to define the role of the PROKR2 heterozygous mutations in isolated hypogonadotropic hypogonadism (IHH), testing the hypothesis that heterozygous mutations in PROKR2 in patients with GnRH deficiency are not sufficient to cause the hypogonadotropic hypogonadism phenotype in isolation, but can contribute to the phenotype in association with a second genetic """"""""hit"""""""".
My second aim i s to elucidate mechanisms by which mutations in conserved amino acids interfere with PROKR2 function to recognize the functions of these amino acids and domains of this receptor and also to identify proteins connected to intracellular trafficking (chaperones) and degradation pathways of GPCRs. Together, these studies will advance our understanding of the etiology of GnRH deficiency and the role of prokineticin system in this process, and will provide insights into the structure-activity relationships of the PROKR2, with potential implications for GPCR biology in general. This work will expand my research training to encompass both a molecular approach to understanding the mechanisms that cause disease and a translational approach in relating my findings to the phenotypes of patients with disorders of reproductive development and function.

Public Health Relevance

The aim of this project is to understand the mechanisms by which mutations in PROKR2, which encodes a G protein-coupled receptor, contribute to disorders of reproductive development. We will identify new genes linked with this disorder and determine structure-function relationships of PROKR2. The successful completion of the proposed studies will advance our understanding of the genetics of GnRH deficiency and may lead to the development of new diagnostic and therapeutic strategies to treat these human disorders.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
International Research Fellowships (FIC) (F05)
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NST-2 Subcommittee (NST)
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Lamar, Charisee A
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Brigham and Women's Hospital
United States
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Bessa, Danielle S; Macedo, Delanie B; Brito, Vinicius N et al. (2017) High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic. Neuroendocrinology 105:17-25
Abreu, Ana Paula; Kaiser, Ursula B (2016) Pubertal development and regulation. Lancet Diabetes Endocrinol 4:254-264
Simavli, Serap; Abreu, Ana Paula; Kwaan, Mary R et al. (2016) Candidate gene analysis in a case of congenital absence of the endometrium. Fertil Res Pract 2:3
Stecchini, Monica F; Macedo, Delanie B; Reis, Ana Claudia S et al. (2016) Time Course of Central Precocious Puberty Development Caused by an MKRN3 Gene Mutation: A Prismatic Case. Horm Res Paediatr 86:126-130
Abreu, Ana Paula; Macedo, Delanie B; Brito, Vinicius N et al. (2015) A new pathway in the control of the initiation of puberty: the MKRN3 gene. J Mol Endocrinol 54:R131-9
Macedo, Delanie B; Abreu, Ana Paula; Reis, Ana Claudia S et al. (2014) Central precocious puberty that appears to be sporadic caused by paternally inherited mutations in the imprinted gene makorin ring finger 3. J Clin Endocrinol Metab 99:E1097-103
Noel, Sekoni D; Abreu, Ana Paula; Xu, Shuyun et al. (2014) TACR3 mutations disrupt NK3R function through distinct mechanisms in GnRH-deficient patients. FASEB J 28:1924-37
Abreu, Ana Paula; Dauber, Andrew; Macedo, Delanie B et al. (2013) Central precocious puberty caused by mutations in the imprinted gene MKRN3. N Engl J Med 368:2467-75
Abreu, Ana Paula; Noel, Sekoni D; Xu, Shuyun et al. (2012) Evidence of the importance of the first intracellular loop of prokineticin receptor 2 in receptor function. Mol Endocrinol 26:1417-27