Pulmonary Hypertension in Human
In human, pulmonary Arterial Hypertension (PAH) is a progressive and often a fatal disorder that characterized by abnormally elevated blood pressure (hypertension) accompanied with a progressive remodeling of the pulmonary arteries, resulting in elevated pulmonary vascular resistance and, eventually, right ventricular failure (Figure 1). PAH affect about 15 – 50 cases/million in the US and Europe. Regardless of the significantly improved management of PAH in the past 15 years, yet the mortality rate is still relatively high, with a 5-year survival rate of 60%. Currently, pulmonary hypertension can't be cured and treatment may help in improving symptoms and slow the progress of the disease.
Figure 2. Ascetic broiler chicken's opened abdominal cavity showing the abundance of ascetic fluid in a condition knowing as " Water belly"
Figure 1. Normal pulmonary artery (left) vs remodeled pulmonary artiery in PH (right).
Pulmonary Hypertension Syndrome in Chicken.
My Latest Research:
My Research Abstract
Pulmonary Arterial Hypertension (PAH) is a progressive disease in humans that causes a characteristic elevation in pulmonary arterial pressure leading to right ventricle congestive heart failure and eventually death. Over the last decade, significant progress has led to substantial improvements toward understanding disease etiology and pathology. Much of this progress was attributed to work with animal models. Although till now there is no acceptable animal model for human PAH that completely recapitulate the human disease, still they do provide an important insights into the cellular and molecular pathways contributing to its development. Our research group has been validating chickens as the medical animal model for human PAH studies. Ascites, an industrial name for PAH in chickens, is a condition which occurs in broiler chickens as a result of elevated pulmonary vascular pressure and ventricular hypertrophy; ultimately leading to heart failure and death. Our research group has developed broiler chicken lines with highly heritability rate for PAH resistance and susceptibility. A previous genome-wide association study identified a region on chromosome 9 associated with susceptibility to ascites that contains the serotonin receptor 5HT2B gene. 5HT2B is a member of the 5-HT serotonin receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) and mediates many of the central and peripheral physiologic functions of 5-HT. The aim of my project is to identify single nucleotide polymorphisms (SNPs) in the 5HT2B gene and establish a possible association of these SNPs with the chicken resistance or susceptibility to acsites . Sequence analysis of the upstream promoter region of 5HT2B revealed 15 SNPs. Some of these SNPs were found to affect potential binding sites for transcription factors. Another SNP, (SNP9093 C<>T transition) was identified located on the 3rd exon that result in a silent mutation and had no effect on protein production or structure. TaqMan assays were developed for some of the identified SNPs to determine the association of 5HT2B gene with susceptibility and resistance to ascites in both experimental and commercial chicken lines. Haplotype tests were performed to asses the linkage among the identified SNPs. Our current data indicate that the SNPs for the promoter 5HT2B gene do not have a significant association with the disease and that they may not serve as reliable QTLs for ascites in chickens. However, in one of the commercial lines, we found that SNP9093 show a significant association to ascetic resistance in chicken. Thus, my current research focus primarily on detecting the allele specific differences of 5HT2B mRNA expression using SNP9093 as the SNP marker in different chicken cell types at different development ages.
Pulmonary hypertension syndrome (PHS) is a significant metabolic disease of fast growing meat-type chickens. PHS occurs when the right ventricle must elevate the pulmonary arterial pressure to overcome increased resistance to flow through restrictive pulmonary arterioles as a response to the high level demand of oxygen in the growing tissue. Ascites is a terminal result of PHS characterized by accumulation of fluids in the abdominal cavity as a consequence of lung and heart failure (Figure 2). In the poultry industry, the economic impact of ascites on worldwide broiler industry is measured in tens of millions of dollars lost per year. Regardless of many years of investigation ascites, still causes financial losses around the world.
Allele-specific gene expression, ASE, is an essential aspect of gene regulation that reveals differences in expression between alleles due to multiple factors such as: epigenetic modification, cis-acting elements, genetic variation, and post transcription modification. In my previous research, I found that SNP9093 show a significant association to ascetic resistance in one chicken commercial line. Thus, currently I am interested in detecting the allelic imbalance in the cDNA from tissues expressing 5HT2B gene at different developmental age. This was done by using the SNP in the 3rd exon coding region of 5HT2B (chr9: 15,205,697 Mbp according to 2015 assembly:C<>T transtion) as a SNP marker to differentiate expression levels between the two alleles. Based on my sequence results and after calculating the ratio between the two alleles, I observed that the T allele had always a slightly higher levels of transcript (over-expressed) than the C allele in all tissues of 2 weeks old chicks. However, this difference in the ratio of the two cDNA alleles was not significant, since all cDNA ratios did not exceed the 60 %:40 % threshold. ASE research are still ongoing on chicken at 6 and 12 weeks of age. To learn more on how to conduct an ASE study for a specific gene, please see the PPT slides below.
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