Category Archives: Transhuman News

PUBLIC RELEASE DATE:

10-Apr-2014

Contact: Lee-Ann Donegan leeann.donegan@uphs.upenn.edu 215-349-5660 University of Pennsylvania School of Medicine

(PHILADELPHIA) Researchers at Penn Medicine have discovered that the tumor suppressor gene folliculin (FLCN) is essential to normal lung function in patients with the rare disease Birt-Hogg-Dube (BHD) syndrome, a genetic disorder that affects the lungs, skin and kidneys. Folliculin's absence or mutated state has a cascading effect that leads to deteriorated lung integrity and an impairment of lung function, as reported in their findings in the current issue of Cell Reports.

"We discovered that without normal FLCN the alveolar epithelial cells (AEC) in these patients' lungs began to die, leading to holes in the lungs that grow as increasing numbers of cells disappear. These holes can fill with air and burst, causing the lungs to collapse," says Vera Krymskaya, PhD, MBA, associate professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, and researcher in the Airway Biology Initiative of the department of Pulmonary, Allergy and Critical Care.

Between 80 and 100 percent of patients with BHD will develop multiple holes or cysts in the lung.

Healthy human alveoli, the terminal ends of the respiratory tree, are lined with type I and type II alveolar epithelial cells (AECs), a renewable population of progenitors in these distal airspaces. AECs are known to maintain pulmonary alveolar homeostasis by regulating gas exchange and fluid transport in the lungs.

Previous studies have shown that there might be some crosstalk between FLCN and the master energy sensor AMP-activated protein kinase (AMPK). AMPK maintains epithelial cell to cell interactions and is essential for epithelial cell survival. It is regulated through LKB1, a tumor suppressor gene associated with 30 percent of lung cancers. E-cadherin, the "zipper" molecule that connects epithelial cells, directs LKB1 to cell junctions and its loss impairs LKB1-mediated AMPK activation. This implies that a loss of or mutation in FLCN can trigger a reaction that can impair AMPK activation, epithelial cell to cell interaction and structure, and as a result, promotes cell death.

Penn researchers set out to examine this hypothesis to determine how and why this occurs.

Krymskaya and her team tested both deleted FLCN in mouse lung type II alveolar epithelial cells and mutated FLCN that lacked normal function in both humans with BHD and mouse epithelial cell systems, and compared them with normal human and mouse control cells.

Read more:
Penn study finds mechanism that regulates lung function in disease Birt-Hogg-Dube syndrome

PUBLIC RELEASE DATE:

10-Apr-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine

PHILADELPHIA The consequences of modern life -- shift work, cell phone addiction, and travel across time zones -- all disturb internal clocks. These are found in the brain where they regulate sleep and throughout the body where they regulate physiology and metabolism. Disrupting the clocks is called circadian misalignment, which has been linked to metabolic problems, even in healthy volunteers.

Researchers from the Perelman School of Medicine at the University of Pennsylvania and the University of Memphis describe in PLOS Genetics the development of new cell models that track and report clock gene function. These engineered cells can be used with inexpensive, off-the-shelf recording devices, making them suitable for small basic labs to large-scale pharmaceutical firms to screen candidate small molecules to help the body's clock function normally.

The team started with liver cells and fat cells because they govern the body's energy processing and storing system and genetically engineered them to flash light with a daily rhythm much like an alarm clock. They validated the cell models and showed that changing clock gene function in these cells is similar to what happens in mice lacking clock genes.

"The previous cellular models were great," says co-senior author John Hogenesch, Ph.D., professor of Pharmacology at Penn. "But these older cell models needed high-end imaging equipment that is out of reach for most labs and early-stage startups." By expanding the number of labs that can do these studies, these models could catalyze better understanding of peripheral clocks, as well as new genetic and chemical tools to improve their function.

"We are very excited about the prospect of using these more physiologically relevant cell-based models for gene and small molecule drug discoveries," says co-senior author Andrew Liu, from the University of Memphis.

###

For more information, visit the University of Memphis FedEx Institute of Technology site summary.

See the original post:
New cell models for tracking body clock gene function will help find novel meds

Contact Information

Available for logged-in reporters only

Newswise (PHILADELPHIA) Researchers at Penn Medicine have discovered that the tumor suppressor gene folliculin (FLCN) is essential to normal lung function in patients with the rare disease Birt-Hogg-Dube (BHD) syndrome, a genetic disorder that affects the lungs, skin and kidneys. Folliculins absence or mutated state has a cascading effect that leads to deteriorated lung integrity and an impairment of lung function, as reported in their findings in the current issue of Cell Reports.

We discovered that without normal FLCN the alveolar epithelial cells (AEC) in these patients lungs began to die, leading to holes in the lungs that grow as increasing numbers of cells disappear. These holes can fill with air and burst, causing the lungs to collapse, says Vera Krymskaya, PhD, MBA, associate professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, and researcher in the Airway Biology Initiative of the department of Pulmonary, Allergy and Critical Care.

Between 80 and 100 percent of patients with BHD will develop multiple holes or cysts in the lung.

Healthy human alveoli, the terminal ends of the respiratory tree, are lined with type I and type II alveolar epithelial cells (AECs), a renewable population of progenitors in these distal airspaces. AECs are known to maintain pulmonary alveolar homeostasis by regulating gas exchange and fluid transport in the lungs.

Previous studies have shown that there might be some crosstalk between FLCN and the master energy sensor AMP-activated protein kinase (AMPK). AMPK maintains epithelial cell to cell interactions and is essential for epithelial cell survival. It is regulated through LKB1, a tumor suppressor gene associated with 30 percent of lung cancers. E-cadherin, the zipper molecule that connects epithelial cells, directs LKB1 to cell junctions and its loss impairs LKB1-mediated AMPK activation. This implies that a loss of or mutation in FLCN can trigger a reaction that can impair AMPK activation, epithelial cell to cell interaction and structure, and as a result, promotes cell death.

Penn researchers set out to examine this hypothesis to determine how and why this occurs.

Krymskaya and her team tested both deleted FLCN in mouse lung type II alveolar epithelial cells and mutated FLCN that lacked normal function in both humans with BHD and mouse epithelial cell systems, and compared them with normal human and mouse control cells.

The control cells showed normal epithelial structure, while the mutated FLCN cells showed irregular and disrupted lung cell structure. In addition, the BHD lungs showed very little FLCN in the type II alveolar epithelial cells.

Read more:
Penn Researchers Determine Mechanism by Which Lung Function is Regulated in Rare Disease Known As Birt-Hogg-Dube ...

Researchers at Penn Medicine have discovered that the tumor suppressor gene folliculin (FLCN) is essential to normal lung function in patients with the rare disease Birt-Hogg-Dube (BHD) syndrome, a genetic disorder that affects the lungs, skin and kidneys. Folliculin's absence or mutated state has a cascading effect that leads to deteriorated lung integrity and an impairment of lung function, as reported in their findings in the current issue of Cell Reports.

"We discovered that without normal FLCN the alveolar epithelial cells (AEC) in these patients' lungs began to die, leading to holes in the lungs that grow as increasing numbers of cells disappear. These holes can fill with air and burst, causing the lungs to collapse," says Vera Krymskaya, PhD, MBA, associate professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, and researcher in the Airway Biology Initiative of the department of Pulmonary, Allergy and Critical Care.

Between 80 and 100 percent of patients with BHD will develop multiple holes or cysts in the lung.

Healthy human alveoli, the terminal ends of the respiratory tree, are lined with type I and type II alveolar epithelial cells (AECs), a renewable population of progenitors in these distal airspaces. AECs are known to maintain pulmonary alveolar homeostasis by regulating gas exchange and fluid transport in the lungs.

Previous studies have shown that there might be some crosstalk between FLCN and the master energy sensor AMP-activated protein kinase (AMPK). AMPK maintains epithelial cell to cell interactions and is essential for epithelial cell survival. It is regulated through LKB1, a tumor suppressor gene associated with 30 percent of lung cancers. E-cadherin, the "zipper" molecule that connects epithelial cells, directs LKB1 to cell junctions and its loss impairs LKB1-mediated AMPK activation. This implies that a loss of or mutation in FLCN can trigger a reaction that can impair AMPK activation, epithelial cell to cell interaction and structure, and as a result, promotes cell death.

Penn researchers set out to examine this hypothesis to determine how and why this occurs.

Krymskaya and her team tested both deleted FLCN in mouse lung type II alveolar epithelial cells and mutated FLCN that lacked normal function in both humans with BHD and mouse epithelial cell systems, and compared them with normal human and mouse control cells.

The control cells showed normal epithelial structure, while the mutated FLCN cells showed irregular and disrupted lung cell structure. In addition, the BHD lungs showed very little FLCN in the type II alveolar epithelial cells.

Next, to evaluate the role of FLCN in the lung, the team isolated the alveolar epithelial cells from the mice with FLCN and deleted the gene in vitro to show the decreased cell to cell interactions and increased cellular permeability. They also examined activity of AMPK in these cells and saw that cells were dying without FLCN, so there was not proper activation of AMPK.

FLCN-deficient mice were also given a doxycycline supplement to conditionally delete FLCN specifically in alveolar epithelial type II cells both during embryonic development and as adults. Newborns experienced developmental changes induced by FLCN deletion in the lung epithelium. Over time, these morphed into changes that resembled emphysema, such as alveolar enlargement and a decline in lung elasticity and pulmonary function.

Here is the original post:
Mechanism that regulates lung function in disease Birt-Hogg-Dube syndrome found