1.Specific Aims: Magnocellular neurosecretory cells (MNCs) located in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus synthesizes and regulates Arginine Vasopressin (AVP) secretion (2, 6, 22, 24, 33, 36, 40, 46). Dysregulation of AVP release leads to dilutional hyponatremia associated with liver and heart failure which increases morbidity and mortality (12, 23, 37, 51, 53, 65). The prevalence of hyponatremia despite treatment with AVP antagonist to increase urine output, improve plasma sodium levels, and reduce ascites is prominent (5, 16, 52, 65).
During high salt loading and dehydration, MNCs has been shown to have upregulation of Brain Derived Neurotrophic Factor (BDNF) (10, 13, 15, 32). BDNF has profound
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Based on these findings, in conjunction with other previous studies, we have developed the following working hypothesis (Figure 1).
Our working hypothesis is highly novel in that it focuses on BDNF from SON can contribute to increased intracellular chloride, which in turn influence changes in AVP release and hyponatremia during liver cirrhosis (Figure 1).
Our hypothesis will be addressed by the following specific aims:
1. To determine the role of BDNF-TrKB signaling in hyponatremia through sustained AVP release during hepatic cirrhosis.
2. To understand the role of estrogen in preventing the chronic activation of vasopressin neurons in female bile duct ligated rats.
These experiments will for the first time define the roles of BDNF-TrkB signaling in the hepatic cirrhosis induced sustained AVP release along with sex differences in the regulation of AVP release. An integrative approach will be employed that includes AAV shRNA knockdown in whole animal experiments, molecular changes in RNA and protein expression, in vitro chloride imaging with ClopHensorN and functional studies of fluid balance and circulating AVP in the rat. These studies will address several critical gaps in the literature by determining the neural adaptations that contribute to pathophysiology in an animal model of dilutional hyponatremia.
2. Background, Significance and Innovation: Dilutional hyponatremia is the most important electrolyte abnormality
Additionally, many chronic liver diseases can lead to cirrhosis. For example, nonalcoholic fatty liver disease (NAFLD) can lead to cirrhosis and is associated with obesity, hyperlipidemia, metabolic syndrome and type 2 diabetes mellitus. Hereditary metabolic disorders such as hemochromatosis and Wilson disease can also lead to cirrhosis (McCance & Heuther, 2014). It seems the cause of cirrhosis is multifaceted. Additionally, many diseases can lead to cirrhosis and it is understandable why the etiology of cirrhosis has not been parsed out, especially because the cause can differ from a
The World Gastroenterology Organization (WGO) has recently declared NALFD as most common cause of liver disease. Obesity is an increasing problem not only in the UK but worldwide. An estimated 26% of the adults in the UK are considered to be obese 1, 2. Obesity induced metabolic syndrome may lead to NAFLD, which can progress to Nonalcoholic Steatohepatitis (NASH), and in turn to advanced fibrosis and an increased risk of Hepatocellular Carcinoma (HCC) 2, 3.
The liver is the largest gland and second largest organ in the human body. It is also the only internal organ capable of regeneration following injury. Located in the abdominal cavity, this reddish brown organ is divided into lobes of different size and shape. The liver plays a critical role in metabolism, digestion, elimination, and detoxification, among other processes. This organ performs a surprisingly large number of functions that influence virtually all other body systems. This is why diseases of the liver can be so devastating. One class of chronic diseases affecting the liver is cirrhosis. (Kasper, 2008)
Liver cirrhosis is a life threatening disease and is irreversible. It is therefore of utmost
Hepatic encephalopathy is a condition that presents to patient with end-stage liver disease. It relates to wide spectrum of neuropsychiatric abnormalities due to the result of neurotoxins such as ammonia accumulates in the bloodstream. Those with chronic liver disease that progress to cirrhosis is common manifestation of acute/fulminant hepatic failure (Gasbarre & Newland. 2012). Patient with HE ranged from abnormal sleep patterns, irritability, and changes in personality/behaviors, impairment in attentions, coordination, or mental function to neurologic symptoms with flapping tremors and/or coma (Chaney. et.,al. 2015).
Liver disease commonly known as Non Alchoholic Fatty Liver Disease (NAFLD) is esstmated to be present in as much as 86% of everyone who suffer from severe obesity. If left untreated, it has the potential to damage thee liver and lead to the development of cirrhosis
Giving the fact that NAFLD is usually an asymptomatic disorder, it is often unrecognized in everyday clinical practice. Namely, most patients with NAFLD have no symptoms, and aminotransferase levels which are used as a marker of liver damage, are within normal values in almost half of all patients. NAFLD is strongly associated with type 2 diabetes mellitus (T2DM) and has been linked to increased cardiovascular disease (CVD) risk. It is characterized by insulin resistance and mitochondrial dysfunction6. Indeed, there is a gradual increase in the severity of insulin resistance in the range of NAFLD which may contribute to the evolution of liver damage. Also, it is associated with an increased risk of kidney disease in subjects with multiple CVD
The progression from fibrosis to cirrhosis, the end-point of CLDs, is distinguished by a prolonged inflammatory and fibrogenic process that leads to an abnormal angioarchitecture distinctive for cirrhosis. Several mechanisms are responsible for the angiogenic switch during the pathogenesis of CLDs. First, CLDs are characterised by chronic inflammation. Increased intrahepatic vascular resistance is primarily caused by anatomical changes, such as fibrotic scar tissue compressing portal and central venules. In addition, the formation of fibrotic septa, as well as sinusoidal capillarisation, can result in an increased resistance to blood flow and oxygen delivery. This results in hypoxia and the transcription of hypoxia-sensitive pro-angiogenic
Humans simply can not live without the liver; it is even in the name “Liver”. The liver is composed of four lobes and is located in the right side of the body. As the heaviest organ, the liver performs a plethora of functions simultaneously. It acts as a refinery by filtering and purifying blood. Moreover, the liver stores carbohydrates by converting it to simple sugars. The liver also takes a major part in digestion by producing bile. Bile is an essential component in processing fats. Bile is originally made in the liver but is stored in the gallbladder. Furthermore, the liver also takes part in the body’s immunity and the production of important blood proteins. Blood is transported to the liver via two vessels: the hepatic artery (blood from the heart), and the hepatic portal vein (blood from the guts). Blood leaves the kidney through the hepatic vein that leads to the heart. For such an important organ, it is no surprise that having a defective
The RAS is a hormone system that is responsible for maintaining homeostasis in relation to vasodilation or vasoconstriction, vascular or cardiac cell growth and mediating oxidative stress. (Vlachogiannakos et. al. 2001) The RAS is under sympathetic nervous control and can be influenced by an individuals weight, diet or amount of insulin. (White 2007) As illustrated by figure 1, The RAS involves the release of angiotensinogen from the liver, which undergoes cleavage by renin to produce Angiotensin I. This is then converted to angiotensin II by ACE. Angiotensin II is a powerful vasoconstrictor as well as being able to induce vascular and cardiac myocyte growth, and increases oxidative stress in cardiovascular and renal tissues. All the effects of angiotensin II assist in
Hepatorenal syndrome(HRS) is a frequent portal hypertension-associated complication of liver cirrhosis (7). HRS has the worst prognosis between all cirrhosis
Despite the scientific progress in the field of liver disorders, hepatic fibrosis still remains a major medical problem with significant morbidity and mortality. Liver fibrosis is a reversible response that occurs in almost all pathological conditions associated with chronic hepatic injury (Malhi and Gores 2007). After a chronic liver injury of any etiology, the damaged hepatocytes, their membrane components, metabolites of toxic agents, and infiltrating inflammatory cells activate Kupffer cells, which release a number of soluble agents, including cytokines, such as platelet-derived growth factor (PDGF), transforming growth factor-b1 (TGF-β1), tumor necrosis factor-α (TNF-α), insulin-like growth factor-1 (IGF-1) and endothelin- 1 (ET-1), as
Liver synthetic functions are assessed by protein and coagulation factors synthesis. Decrease in protein synthesis affects albumin .nevertheless; albumin is not specific or sensitive enough to detect compromised function. Protein loss with ascites might decrease albumin levels; so
liver damage and mitochondrial dysfunction will follow which contribute to fat accumulation and development of NAFLD.9
serum (T3).Objectives: to investigate the relation of these hormonal alterations to esophageal varices, portal hypertensive gastropathy