While the compounds in hand (C608, C562) will allow for the first pharmacological examination of PAR2-biased signaling in an asthma model, experiments with PAR2-modulators that preferentially block -arrestin/MAPK PAR2 signaling will be prioritized as they are developed in our independently funded drug-dicovery program.
c.2 Specific Aim 2: Determine the impact of modulation of PAR2 signaling using in vivo models of allergic asthma. Our preliminary data show PAR2 signaling activates two signaling pathways with biased activation potentially leading to either inflammation or bronchorelaxation. The focus of these experiments will be to determine how PAR2 modulation (activation, inhibition, or biased activation/inhibition) impacts inflammatory responses and lung resistance based on the disparate roles of these pathways activated by PAR2.
There are several strengths of Specific Aim 2 that will allow us to understand the role of PAR2 in asthma by studying the specific pathways of PAR2 signaling. We have an existing set of PAR2 activity modulat...
... middle of paper ...
...nce is reduced by cotreatment with the PAR2 inhibitor C391 (Figure 15). Taken together, these show that localized inhibition of PAR activity in the lung during allergen exposure is sufficient to mitigate inflammation, mucus production, and lung resistance, all critical components of asthma. We demonstrate the feasibility to perform these studies with other PAR2 modulators including biased agonists and to investigate the role of PAR2 modulation in severe asthma and asthma caused by allergens that are not associated with protease activity. These preliminary data show that the outcomes planned are relevant both to PAR2 modulation and to lung physiology and immunology. They also show that our laboratory has the expertise to perform these experiments with the precision to interpret subtle differences in lung immunology and physiology caused by PAR2 modulating compounds.
Need Writing Help?
Get feedback on grammar, clarity, concision and logic instantly.Check your paper »
- During the last few years, most of the societies, all over the world, have been facing a progressive increase of adverse reactions to food. Accordingly, as many as 20-30% of the general population, in the gross, report some two adverse reactions to food components, of which, for the most part, allergic disorders are of considerable concerns owing to their epidemic increase in prevalence and morbidity. Taken together, allergic diseases constitute one of the major problems of modern day medicine. Currently, numerous strategies for definitive treatment are being studied, including sublingual/oral immunotherapy, injection of anti-IgE antibodies, cytokine/anti-cytokine therapies, Chinese herbal t... [tags: human physiology, food hypersensitivity]
1513 words (4.3 pages)
- ... Unfortunately, this may also impose massive hardships by increasing the costs and labor for agencies to establish permissible access. However, this expected and justified expense comes with risk reduction. It is also worth noting that FISMA protects certain government information from being subjected to release by the Freedom of Information Act (FOIA) (Feinberg, 2004). GLBA repealed acts such as the Glass-Steagall Act of 1933 and the Bank Holding Company Act of 1965, which barred financial bodies from performing any mixture of roles such as banks delving into insurance underwriting, securities, and other investment functions (Mamun, Hassan, & Maroney, 2005).... [tags: information security, models, protection]
1683 words (4.8 pages)
- INTRODUCTION Marketing is one of the vital functions of any organisation. The marketing efforts enables the firm’s products to be visible and desired by customers. Marketing decisions can be made based on certain predefined theories and models, that enable a marketer to make an educated decision (Van Bruggen and Wierenga 2000). The term ‘marketing model’ refers to any diagrammatic, mathematical or tabular representation of information that can provide insights to the user in a logical manner (Lazer 1962).... [tags: Marketing Decision Models]
2835 words (8.1 pages)
- Introduce the concept of using information security models (why are they important). Two fundamental concepts in computer and information security are the security model, which outlines how security is to be implemented. Basically providing a blueprint and the architecture of a computer system, which fulfills this blueprint. A security model is a statement that outlines the requirements necessary to properly support and implement a certain security policy. A security model provides a deeper explanation of how a computer operating system should be developed to properly support a specific security policy (Whitman, 2014).... [tags: Computer security, Access control, Computer]
747 words (2.1 pages)
- In this paper, an individual with a psychological problem will be presented, and the reason for her problem will be explained using six different theoretical models. The anonymous individual that is the focus of this paper suffers from anxiety. The anxiety started in her teenage years and led to several abnormal behaviors, including pulling out her eyebrows and eyelashes until they would not grow back, and hoarding in her adult years. The hoarding causes distress within her home, marriage, and amongst other family members who wish to help.... [tags: Selective serotonin reuptake inhibitor]
1079 words (3.1 pages)
- Most investigations using transgenic animal models of Alzheimer’s disease (AD) have reported a decrease in hippocampal neurogenesis. Currently, is considered that an impairment in neurogenesis can be an important factor during the onset and progression of AD. Most authors consider hippocampal neurogenesis necessary to maintain hippocampal cognitive abilities, therefore, a damage in the proliferative system has to be functionally detrimental (See references in Mu and Gage, 2011). Most animal models with the familial type mutations that cause AD show that when toxic amyloid beta peptides (Aβ42) are present, hippocampal neurogenesis decreases.... [tags: using transgenic animal models]
1012 words (2.9 pages)
- Asthma, one of the most common lung diseases, affects 300 million individuals around the world today. (Global Initiative for Asthma, 2012) However, what exactly is this ailment, which affects so many people. Asthma is a prolonged disease that constricts the airways in the lungs. “There are air-conducting passageways: left bronchus and right bronchus and many small air passageways they branch into, the bronchioles, which deliver air to the lungs.” (Krogh, 2011, p. 584) While normal functionality of the lungs carries oxygen through these passageways, during an asthma attack, the bronchioles become inflamed and constrict the flow of oxygen.... [tags: Lung, Disease, Epidemiology]
1508 words (4.3 pages)
- Part 1: General Review of Signalling a.) Explain the fundamental differences of analog and digital signalling. Baher (2001, p. 2) states that the natural world we live in, as well as most artificial sources, produce signals which we have grown accustomed to consider mainly of the analog type. This means that the signal f (t) is defined, somehow, for all values of the continuous variable t, and its amplitude can assume any value of a continuous range. Such a signal is referred to as an analog signal.... [tags: Signalling, electronics,]
1245 words (3.6 pages)
- Channel Signaling Systems: Channel signaling systems are communications systems that are used for controlling, accounting for, and managing traffic during communication. Generally, signals are transmitted between controllers either over the talking route or over different data networks. One of the most commonly used paths is telecommunications networks that provide various methods of developing and bringing down circuit links like signaling. Signals can be classified into four major functions i.e.... [tags: telecommunication, frequency, voice]
1130 words (3.2 pages)
- Signaling System 7 The international Engineering Consortium defines Signaling System 7 (SS7) as "a style of architecture for performing out-of-band signaling in support of the call-establishment, billing, routing, and information-exchange functions of the public switched telephone network (PSTN). It identifies functions to be performed by a signaling-system network and a protocol to enable their performance." In this brief glimpse into SS7, we will try to deliver a useful overview of the many elements and core competencies that make up Signaling System 7.... [tags: Papers]
4271 words (12.2 pages)
- Factors That Determine The Optimal Concentrations Of Par2
- Should College Athletes Be Paid?
- The Great Illusion By Norman Angell
- Collaboration Between A General Education Teacher And A Special Education
- Cross Cultural Misunderstandings Between Chinese Mnc 's And Local Human Resource Development Sub Saharan Africa
- Netflix And The Video Service