Felicia V. Nowak, M.D., Ph.D.
Associate Professor of Molecular Endocrinology
Department of Biomedical Sciences
nowak@ohiou.edu
Academic & Research Center 202E
740-593-2223
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Introduction to Neuropeptides
 
The organization and ultimate normal function of the adult mammalian brain reflects the orchestration of extensive cellular migration, selective survival and differentiation during development. Many neuronal cells have the potential to display a seemingly endless array of phenotypes and thus retain a degree of functional plasticity throughout life. Understanding the roles of individual gene products, including neuropeptides, in this process will enhance our understanding of normal brain development. It will also expand our capacity to manipulate brain function in disease states.

Many neuropeptides are widely expressed and some of them exhibit multiple functions. Often the specific function observed is a result of the timing and location of expression. Hormones can also profoundly affect gene expression, incuding neuropeptide gene expression.
   
The preoptic regulatory factors, PORF-1 and PORF-2  
   
My laboratory is focused on studying the functions and mechanisms of action of two neuropeptide genes, the preoptic regulatory factors, PORF-1 and PORF-2. These genes give rise to two unique peptides which are expressed in the mammalian brain and whose expression is regulated by age, gender and hormonal status in a brain region dependent manner. Areas of special interest include the hypothalamus, a major regulatory region for neuroendocrine and metabolic functions and the hippocampus, a key area in learning and memory.  
   
Brain Development and Neurogenesis  
   
PORF-1 and PORF-2 may be involved in gender specific development and function of the hypothalamus and hippocampus. Like many neuropeptide factors that are expressed highly during development, PORF-2 and PORF-2 may also play a role in adult neurogenesis. Neurogenic factors may play an important role in brain recovery from injury and insults such as strokes. They also have pharmaceutical potential in the treatment of neurodegenerative diseases such as Alzheimer's and Parkinson's Diseases.

Figure One. Northern blot analysis of PORF-1 and PORF-2 messenger RNA in rat hypothalamus during development. (From FV Nowak and AC Gore. Perinatal Developmental Changes in Expression of the Neurpeptide Genes Preoptid Regulatory Factor-1 and Factor-2, Neuropeptide Y and GnRH in Rat Hypothalamus. Journal of Neuroendocrinol 11:951-958, 1999.) E18-19 = embryonic day 18 to 19, PO = date of birth, P5, P10, P15 = postnatal days 5, 10, and 15, F = female, M = male.

 
   
PORF-1 May be a Transcription Factor  
   
Based on its structure, PORF-1 is thought to be a transcription factor. One of the genes that it regulates may be the type 2 iodothyronine deiodinase (dio2). Dio2 is a key enzyme in the conversion of thyroid hormone to its active form in the central nervous system. Thyroid hormone activiation is essential for normal motor and cognitive function and for CNS development. We are currently investigating the role of PORF-1 in the regulation of this and other genes. The experimental approaches include recombinant protein expression, DNA binding assays and subcellular localization of PORF-1.

Figure Two. Structure of PORF-1. (From FV Nowak, Expression and Characterization of the Preoptic Regulatory Factor-1 and -2 Peptides. Regulatory Peptides 115:179-185, 2003.) TAD = transcription activation domain, LZ = leucine zipper, DBD = DNA binding domain, nls = nuclear localization signal, Se-C = selenocysteine.

 
   
PORF-2 is a Growth Factor  
   
We believe that PORF-2 is a growth factor. Several lines of evidence support this hypothesis. PORF-2 is expressed in several cell types that are rapidly dividing, including skin fibroblasts, immature germ cells in the testes and the placental growth cone. In addition, cells which are transfected and express high levels of PORF-2 show an increase in cell number as well as an increase in thymidine incorporation, indicating that DNA synthesis and cell division are stimulated.

Figure Three. Structure of PORF-2. (From FV Nowak, Expression and Characterization of the Preoptic Regulatory Factor-1 and -2 Peptides. Regulatory Peptides 115:179-185, 2003.) Residues shown in bold are potential phosphorylation sites for protein kinase C (T52) and casein kinase 2 (T22 and S69).

 
   
Current work in the lab includes the screening of a mouse genomic library to identify PORF-2 clones. These clones will be used to make constructs to engineer null or so-called "knock-out" mice. The knock out mice can be used to assess the effects of PORF-2 on growth and development, including brain development. We may see effects in rapidly dividing cells, such as skin and intestines. We also may see effects on fertility (germ cell expression) and fecundity (placental growth cone).  
   
Expression of PORF-1 and PORF-2 are Modified by a Variety of Hormones  
   
Early on, it was shown that PORF-1 and PORF-2 expression is altered by gonadal hormones, including estrogen and progesterone in females and probably testosterone in males. More recently it has been demonstrated that hydrocortisone and insulin also affect the expression of PORF-1 and PORF-2 in cultured cells. Experiments are ongoing to further quantify and characterize these effects, including the intracellular signalling pathways that are involved.

Current work in the laboratory also involves DNA sequence analysis of the 5' promoter and regulatory regions in the porf-1 and porf-2 genes responsible for the observed hormonal effects.

Figure Four. DNA sequence of a segment of the porf-1 gene.

 
   
   
   
  Ohio University
Heritage College of Osteopathic Medicine
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Last updated: 04/03/2014