The Treatment Of Acute Rheumatic Fever Biology Essay

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I have a dream to work in the field of medicine, particularly cardiovascular science since my childhood. A large influence in the decision was my grandmother, who died because of rheumatic heart disease. Therefore, I was curious about field cardiovascular pharmacology and pharmacy and sincerely hope to find out efficient treatments for heart diseases. With extensive interest in cardiovascular medicine and the desire to help those suffering from heat disease like my grandmother, I chose to study Biomedical Engineering as my major in bachelor degree and go on studying Biotechnology with master degree in University of Glasgow. Now, I am applying a PhD project which is relative to cardiovascular and metabolic research by Dr. Eva Hoi-Ching Tang.

Background Knowledge:

Cyclooxygenase-2-derived prostanoids, known as multifunctional physiologic factors, are synthesized from arachidonic acid and produced by various stimuli and involve in local homeostasis as well as physiological responses. They can possess a wide range of physiological functions and modulate inflammatory diseases [4] [5]. Prostaglandin E2 (PGE2) is a member of major cyclooxygenase-2-derived prostanoids, and usually consists of 20 carbon atoms including a 5-carbon ring. Many studies have shown that PGE2 plays a significant role in response to inflammation stimuli. It exerts function mainly through four E prostanoid receptors subtypes-EP1, EP2, EP3, and EP4, which are all belonging to seven transmembrane G protein-coupled receptors but with different signaling [5][7]. EP1 couples to Gq and increase of cAMP, while EP3 can couple to Gi so that inhibiting the increase of cAMP. Both EP2 and EP4 receptors can stimulate agenylyl cyclase, leading to the elevation of intracellular cAMP [4]. Recent research found that PGE2, through binding to EP4 receptor, has ability to suppresse the production of inflammatory cytokines and chemokins in macrophage and T lymphocyte that involve in innate and adaptive immunity as well as tissue remodeling and repair, which therefore exerts anti-inflammatory effects [5][6].

Traditionally, the action of EP4 largely depends on a Ga-protein-mediated transient increase in intracellular cAMP, and then cAMP activates protein kinase A (PKA) and phosphorylates cAMP response element-binding protein (CREB) so that enhancing the transcription of downstream genes (see Fig. 1a). Nevertheless, in the anti-inflamatory pathway, The EP4 receptor-associated protein (EPRAP) can bind to the cytoplasmic tail of EP4 so that reducing phosphorylation and enhancing the stability of p105, a cyroplasmic inhibitor of the activation of nuclear factor kaooa B (NFkB) and mitogen-activated protein kinase kinase (MEK), which thus attenuates the cellular effects of NFkB and MEK and further reduces their down stream inflammatory gene transcription and the production of proinflammatory factors (see Fig. 1b) [5].

Fig. 1 Principles of the traditional EP-mediated pathway and the EP4 mediated anti-inflammation pathway; a: Prostaglandin E2 through EP4 receptors stimulates agenylyl cyclase and based on activation of adenyly cyclase, the activated PKA phosphorylates cAMP response element-binding protein (CREB) and eventually enhances the transcription of downstream genes; b: EP4-associated EPRAP can suppress the phosphorylation of p105 so that improving the stability of p105, which further inhibits NFkB and MEK activation and thus reduces pro-inflammatory gene transcription [5].

Because of the anti-inflammatory ability, EP4 has become a key candidate in treating chronic inflammatory disorder diseases. In order to further investigate the role of EP4 in inflammation and its in vivo function, Tang and colleagues recently examined EP4 in two types of cardiovascular diseases that all belong to chronic inflammatory disorder diseases, and revealed that deficient in EP4 on bone-marrow-derived cells can accelerate local inflammation in atherosclerotic lesions in vivo and enhance the prevalence of abdominal aortic aneurysm (AAA) in vivo formation [6][7].

Overall, EP4 agonism may contribute to efficiently producing powerful anti-inflammatory actions in response to inflammatory disorder diseases. Moreover, EP4 is also attractive to attenuate syndromes related to inflammation, such as the reduction of inflammatory reactions in allograft cardiac transplantation as well as tissue damage after myocardial ischemia.

Research Proposed Programs:

In the future, I am willing to focus on two novel and meaningful research directions; one is the potential use of EP4 agonist in treating acute rheumatic fever, a main cause of rheumatic heart disease; the other is the potential use of EP4 agonist in metabolic obesity. In the following part, I will provide a general description of why I choose those two proposed programs, and why those programs are deserved to be done.

The potential use of EP4 agonist in the treatment of acute rheumatic fever

Acute rheumatic fever is a serous inflammatory disease that occurs following a streptococcus pyogenes infection and believed to be caused by antibody cross-reactivity that can involve the heart, joints, skin and brain. It typically develops two or three weeks after infections and commonly appears in children between the ages of 6 and 15. One of the most dreaded complications of rheumatic fever is rheumatic heart disease. 30% ~ 45% of acute rheumatic fever patients will develop into heart inflammation, which eventually forms chronic rheumatic heart disease and leads to heart failure. Acute rheumatic fever often produces inflammation of the heart (carditis) and once rheumatic valvular disease begins, it tends to continually worsen over time. Repeated episodes of rheumatic fever can accelerate the deterioration of the heart valves. Currently, the most common treatment for acute rheumatic fever is by using anti-inflammatory to reduce inflammation such as aspirin or corticosteroids. In addition, the continual use of low-dose antibiotics such as penicillin, sulfadiazine or erythromycin is also necessary in order to the prevention of recurrence. However in children and teenagers, the use of aspirin and aspirin-containing products can be associated with Reye's syndrome, a serious and potentially deadly condition, the risks, benefits and alternative treatments must always be considered when administering aspirin and aspirin-containing products in children and teenagers.

As revealed from previous research, we have strong evidences to believe that EP4 agonism is a powerful and effective tool in anti-inflammatory actions. So EP4 agonism is attractive in becoming an alternative treatment of acute rheumatic fever. Future necessary research may aim at the test of EP4 agonism potential role in inflammatory reactions of acute rheumatic fever.

The potential use of EP4 agonist in the treatment of metabolic obesity

Obesity currently is a highly prevalent condition and heterogeneous with regard to its impact on cardiovascular disease risks [3]. The discovery that obesity itself results in an inflammatory state in metabolic tissues suggested that the state of chronic low-grade inflammation associated with excess adipose tissue may explain the development of the obesity-related pathologies, such as type 2 diabetes mellitus and cardiovascular disease [1][2].

As EP4 agonism has been proved that is effective in anti-inflammatory actions, it may become another anti-inflammatory therapy for its potential in the treatment of obesity-related insulin resistance and glucose intolerance.

There are still many problems needed to be solved during the investigations of those two proposed programs and I sincerely hope I will have valuable opportunities to do research in cardiovascular and metabolic area. I additionally hope through my research, there will be a novel and efficient treatment of cardiovascular and metabolic diseases.