Penn Dental Medicine Professor Unlocks the Mysteries of Mast Cells – Penn: Office of University Communications

Mast cells, components of the immune system, are responsible for alleriges and asthma, conditions that debilitate millions. Yet relatively few scientists study them.

Hydar Ali of the University of Pennsylvania is a member of the select group of researchers for whom mast cells are a focus. A professor in the Department of Pathology and director of faculty advancement and diversity in Penns School of Dental Medicine, Ali has spent his career discerning the cells unique qualities and honing in on strategies to modulate their activity to improve health.

Obviously Im biased, but I do think that our findings are critically important, Ali said. These cells are relatively poorly understood, and yet weve been able to identify some of the most sought-after molecular targets to affect diseases like allergies and asthma that have the potential to kill.

Mast cells are part of the immune system and reside in tissues rather than in the blood stream. They are important for protecting the body from pathogens and contribute to wound healing but are most notorious for their involvement in inflammatory and allergic conditions. They are rich in histamine which is released when mast cells are activated and can lead to the quintessential signs of an allergic reaction: hives, itching and even anaphylaxis.

No living human has ever been shown to lack mast cells, and mutant mice that lack them are unable to fight microbial infection, said Ali, so its pretty clear that mast cells are there to protect us from infection. But the other side of the coin is that people who have too many mast cells can develop skin rashes, itch, nausea, vomiting, diarrhea and abdominal pain.

Because mast cells are present only in low numbers and cannot be extracted from the tissue, they are considered difficult to work with, and thus the pool of researchers who do so is limited.

Despite these hurdles, Ali started working with mast cells while pursuing his doctorate at University College London. His dissertation examined the diversity of mast cell types.

I looked at mast cells from different tissues and found tremendous heterogeneity, he said. So, for example, if you took a mast cell from the gut, that cell is different from one in the skin. Theres also variability when you go to different species, so there are major differences between mouse mast cells, rat mast cells and human mast cells.

These differences make translational work, moving from animal models to human treatments, a challenge, as Ali and many of his colleauges in the field have discovered.

After earning his Ph.D., Ali moved into a postdoctoral position at the National Institutes of Health, where a handful of labs focused on mast cells. He recalls headline-making news when scientists in a neighboring lab cloned the gene for the IgE receptor. This receptor binds IgE antibodies and triggers a signaling pathway associated with allergic diseases, eczema and other condtions.

I remember The New York Times said that a therapy for asthma was on the way, Ali said. You read so many things like this and they never come, but this was different.

Indeed, by the 2000s an asthma drug came on the market to target this receptor

Ali saw that the field was ripe for discovery. Wanting to continue his rearch in academica, he took a position at Duke University, working with Ralph Snyderman, who was then chancellor of health affairs. Snydermans research portfolio primarily examined white blood cells other than mast cells, notably neutrophils and macrophages, but Ali helped discover that mast cells could be used as a model system to study properties of neutrophil receptors in a different context.

In 1998, Ali was ready to run his own lab. He had had the good fortune of being awarded grants, from the NIH, American Lung Association and American Heart Association, all to study G protein coupled receptors, which, like IgE receptors, are present in large numbers on mast cells.

At Duke, he had discovered that one of these G-protein coupled receptors, or GPCRs, was activated by a protein called C3a, part of the complement pathway that can often promote inflammation. High levels of C3a was also known to be associated with an increased risk of asthma in humans.

After coming to Penn, Ali serendipitously discovered the presence of a new GPCR, known as MRGPRX2, which is found only on mast cells and not other immune cells.

Pursuing this finding led Ali and colleagues to find that small proteins called antimicrobial peptides, which were believed to only kill microbes directly, could activate mast cells through MRGPRX2 to harness the protective function of mast cells to help clear the invading microbes.

Working with Penn Dentals Henry Daniell, a professor in the Department of Biochemistry,Ali showed that a couple of these antimicrobial peptides, manufactured through Daniells patented biopharmaceutical plant-production platform, were able to activate the mast cells through MRGPRX2, showcasing the positive role of mast cells in defending the body against pathogens.

I think this highlights the fact that mast cells are playing a role in host defense, said Ali.

On the other side of this fine line, mast cells involvement in pathogenic conditions such as asthma, Alis lab has been at the forefront in discoveries with the potential to translate to human therapies.

Earlier researchers had found that a key receptor involved in chronic asthma and anaphylaxis in mice did not function the same way in humans. Thus much energy that was poured into developing inhibitors of that receptor in mice ended up being fruitless in the pursuit of human therapies.

Yet, Ali and colleagues showed that, in humans, similar effects were elicited by signaling through MRGPRX2. While they had also shown that activating this receptor led to improved antimicrobial effects, in the context of allergic response, blocking this receptor could inhibit the harmful inflammatory effects.

Its two sides of the same coin, Ali said.

With a new set of grants, Alis lab is working with the Fox Chase Chemical Diversity Center to screen for small molecules that mimic known antimicrobial peptides in activating mast cells through the MRGPRX2 and operate with a similar dual function, direct killing and activating mast cells to help in fending off the attack. Theyre also looking for potential drugs that block this receptors activity to reduce the effects of allergic and chronic inflammatory conditions.

In addition, theyre using mouse models that use human version of molecular receptors to continue unraveling the mysteries of mast cells. One project is looking at the association between MRGPRX2 actviation and worsening asthma, while another is looking at the connection between chronic heart and lung diseases and genetic variations in mast cell receptors.

The goal is keeping the work relevant to humans.

With animal models, Ali said, if you think a gene is important, you knock it out, you over express it, you generate a ton of data and can publish it in a very high-impact journal. And when you submit a grant, it looks like youre a very productive investigator, you have impressive results in mice. But the question is, does it relate to humans?

In May, Ali will present his recent findings on the mysteries of controlling mast cells through MRGPRX2 in a keynote lecture at the European Mast Cell and Basophil Research Network International Meeting in Prague.

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Penn Dental Medicine Professor Unlocks the Mysteries of Mast Cells - Penn: Office of University Communications

Targeting cancer stem cells improves treatment effectiveness and … – UCLA Newsroom

Targeting cancer stem cells may be a more effective way to overcome cancer resistance and prevent the spread of squamous cell carcinoma the most common head and neck cancer and the second-most common skin cancer, according to a new study by cancer researchers at the UCLA School of Dentistry.

Head and neck squamous cell carcinoma is a highly invasive form of cancer and frequently spreads to the cervical lymph nodes. Currently, cisplatin is the standard therapeutic drug used for people with HNSCC. Yet, more than 50 percent of people who take cisplatin demonstrate resistance to the drug, and they experience a recurrence of the cancer. The five-year survival rates remain sorely low and researchers still dont understand the underlying mechanisms behind head and neck squamous carcinoma. Therefore, said UCLA cancer biologist Dr. Cun-Yu Wang, who led the study, theres an urgent need to understand why people with this type of cancer are resistant to therapy and to develop new approaches for treating it.

Wangs researchis published online today in the peer-reviewed journal Cell Stem Cell.

Cancer stem cells are known to be responsible for tumor formation and development; they also self-renew and tend to be unresponsive to cancer therapy. These cells have been found in head and neck squamous cell carcinoma. Given the unique challenges that cancer stem cells pose for oncologists, it remains unclear what the optimal therapeutic strategy is for treating HNSCC.

To address this, Wang, who holds the Dr. No-Hee Park Endowed Chair in Dentistry at UCLA and holds a joint appointment in the UCLA Department of Bioengineering, and his research team first developed a mouse model of head and neck squamous cell carcinoma that allowed them to identity the rare cancer stem cells present in HNSCC usingin vivolineage tracing, a method to identify all progeny of a single cell in tissues.

The researchers found that the cancer stem cells expressed the stem cell protein Bmi1 and had increased activator protein-1, known as AP-1, a transcription factor that controls the expression of multiple cancer-associated genes. Based on these new findings, the UCLA team developed and compared different therapeutic strategies for treating head and neck squamous cell carcinoma. They found that a combination of targeting cancer stem cells and killing the tumor mass, consisting of high proliferating cells, with chemotherapy drugs resulted in better outcomes.

The team further discovered that cancer stem cells were not only responsible for squamous cell carcinoma development, but that they also cause cervical lymph node metastasis.

This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice, said Wang, who is a member of the UCLA Jonsson Comprehensive Cancer Center and of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. Our discovery could be applied to other solid tumors such as breast and colon cancer, which also frequently metastasizes to lymph nodes or distant organs.

With this new and exciting study, Dr. Wang and his team have provided the building blocks for understanding the cellular and genetic mechanisms behind squamous cell carcinoma, said Dr. Paul Krebsbach, dean of the UCLA School of Dentistry. The work has important translational values. Small molecule inhibitors for cancer stem cells in this study are available or being utilized in clinical trials for other diseases. It will be interesting to conduct a clinical trial to test these inhibitors for head and neck squamous cell carcinoma.

Additional authors of the study include Demeng Cheng, first author and postdoctoral scholar in Wangs lab; Mansi Wu, Yang Li, Dr. Insoon Chang, Yuan Quan, Mari Salvo, Peng Deng, Dr. Bo Yu, Yongxin Yu, Jiaqiang Dong, John M. Szymanski, Sivakumar Ramadoss and Jiong Li who are all from the laboratory of molecular signaling in the division of oral biology and medicine at the UCLA School of Dentistry.

This work was supported in part by the National Institute of Dental and Craniofacial Research grants R37DE13848, R01DE15964 and R01DE043110.

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Scientists identify a key barrier to proliferation of insulin-producing cells – Medical Xpress

March 9, 2017 Rohit Kulkarni, M.D., Ph.D., Senior Investigator at Joslin Diabetes Center, and Professor of Medicine at Harvard Medical School. Credit: John Soares

If you become resistant to insulin, a condition that is a precursor to type 2 diabetes, your body tries to compensate by producing more of the "beta" cells in the pancreas that produce the critical hormone. Researchers have long sought to understand why these cells often fail to proliferate in people who go on to develop the disease. Studying both humans and mice, scientists at Joslin Diabetes Center now have pinpointed one key biological mechanism that can prevent the cells from dividing successfully.

Better understanding of the beta-cell proliferation process eventually may lead toward therapies for diabetes patients, whose supplies of these cells often shrink over time, says Rohit Kulkarni, M.D., Ph.D., a Joslin Senior Investigator and senior author on a paper about the work published in the journal Cell Metabolism.

Previous studies of beta cell proliferation generally have focused on mechanisms that kick off the cell cycle that leads to successful cell division. "Most adult mammalian beta cells are in a quiescent phase, and so if you want to push them into the cell cycle, you need to shake them out of their sleep," explains Kulkarni, who is also a Professor of Medicine at Harvard Medical School. Over the years, scientists have discovered a number of biological mechanisms that help to initiate the cell cycle.

"However, very often many of the beta cells that begin the cell cycle don't complete it, because the regulatory signals aren't appropriate," Kulkarni notes. "The cells choose to die because that's an easier route than completing the cell cycle."

Seeking to understand this failure to divide, his lab previously analyzed beta cells that were modified to lack an insulin receptor and didn't divide as easily as normal beta cells. Among their findings, the scientists saw that these cells generated significantly smaller amounts than normal beta cells of two proteins that partner to help separate the cell's chromosomes just before the cell divides.

In their latest research, the Joslin team performed many experiments to explore the actions of these two proteins, called centromere protein A (CENP-A) and polo-like kinase-1 (PLK1), in mice and in cells from humans and mice.

Among their experiments, the researchers studied beta cell signaling in mice that were modified to lack expression of the proteins and experienced insulin resistance by being placed on a high-fat diet, or aging, or becoming pregnant. "We showed that mice that lacked the CENP-A protein could not compensate for insulin resistance by making more insulin-secreting cells," Kulkarni says.

Additionally, his team examined human beta cells and found lower levels of CENP-A and PLK-1 proteins in cells from donors with diabetes compared to cells from healthy donors.

To better understand how insulin signaling affects beta-cell growth, the Joslin scientists next studied a pathway involving a protein called FOXM1. This protein acts as a "transcription factor" that regulates genes by binding to their DNA regions. FOXM1 helps to drive cell proliferation, and it can promote the expression of CENP-A and PLK-1.

"We found that insulin signaling can initiate the binding of this transcription factor with PLK-1 and CENP-A, in both mouse and human beta cells," Kulkarni says. "This binding is lost in beta cells lacking the insulin receptor, and the loss of binding leads to cell death rather than division."

"We also discovered that this type of regulation is, interestingly, specific to beta cells, and not seen in other metabolic cell types such as liver and fat cells," he says.

Given this new insight into how beta cells divide or fail to divide, "our next step will be to begin to ask whether we can target FOXM1 or other proteins in the pathway to enable a better progression through the cell cycle and to generate more beta cells," Kulkarni says.

The research may hold the eventual promise of treatments not only for type 2 diabetes but for type 1 diabetes, in which beta cells are wiped out by autoimmune attack, he adds.

Joslin's Jun Shirakawa was first author on the paper. Other contributors, all from Joslin, included Megan Fernandez, Tomozumi Takatani, Abdelfattah El Ouaamari, Prapaporn Jungtrakoon, Erin Okawa, Wei Zhang, Peng Yi and Alessandro Doria. The National Institutes of Health provided lead funding for the study.

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Interval training exercise could be a fountain of youth – CNN

"Any exercise is better than being sedentary," said Dr. Sreekumaran Nair, senior author of the study and a diabetes researcher at the Mayo Clinic in Rochester, Minnesota. However, Nair noted that high-intensity interval training (HIIT), in particular, is "highly efficient" when it comes to reversing many age-related changes.

High intensity interval training involves short bursts of intense aerobic activity within a stretch of more moderate exercise: intermittently sprinting for 30 seconds, for example, in the middle of a moderate-pace jog.

For the National Institutes of Health-funded study, Nair and his colleagues enlisted the help of both men and women from two age groups: The "young" volunteers ranged in age from 18 to 30; "older" volunteers ranged in age between 65 and 80. Next, the researchers divided these participants into three mixed-age groups and assigned each a different supervised exercise training program lasting three months.

The high-intensity interval training training group did three days a week of cycling, with high-intensity bouts sandwiched between low-intensity pedaling, and two days a week of moderately difficult treadmill walking. The strength training group performed repetitions targeting both lower and upper body muscles just two days each week. Finally, the combined training group cycled (less strenuously than the first group) and lifted weights (fewer repetitions than the second group) for a total of five days a week.

There were clear differences, then, in the amount of time different participants spent in the gym.

Before and after each training session, the researchers assessed various aspects of each volunteer's physiology, including body mass index, quantity of lean muscle mass and insulin sensitivity, one indication of diabetes. The researchers also did routine biopsies of each volunteer's thigh muscles and performed a biochemical analysis in order to establish a comprehensive fingerprint of the muscle.

Analyzing the gathered data, Nair and his colleagues found that all forms of exercise improved overall fitness, as measured by cardiorespiration, and increased insulin sensitivity, which translates into a lower likelihood of developing diabetes. Although all exercise helped with musculature, strength training was most effective for building muscle mass and for improving strength, which typically declines with age.

Meanwhile, at the cellular level, high-intensity interval training yielded the biggest benefits.

Specifically, in the HIIT group, younger participants saw a 49% increase in mitochondrial capacity, while older participants saw a 69% increase. Most cells in our bodies contain infrastructure known as mitochondria. These "organelles" -- a mini-version of an organ within a cell -- perform as tiny batteries do, producing much-needed energy.

Interval training also improved volunteers' insulin sensitivity more than other forms of exercise. Drilling down deeper, Nair and his colleagues compared the protein-level data gathered from participants to understand why exercise provided these benefits.

If we think of the cell as a corporate hierarchy, genes (DNA) are the executives issuing orders to their middle managers: messenger RNA. Tasked with transcribing this order, the RNA turns to ribosomes, which perform a supervisory role by linking amino acids in order to assemble protein molecules. Finally, the proteins, cellular work horses, carry out the task originally dictated by the gene.

"Proteins sustain environmental damage and the damaged proteins have to be ... replaced with newly synthesized (produced) proteins," explained Nair in an email. "With aging in sedentary people, production of many protein molecules decline. ... Gradually the quantity of these protein molecules decrease causing functional decline."

Analyzing the muscle biopsies, the researchers discovered that exercise boosts cellular production of mitochondrial proteins and the proteins responsible for muscle growth.

"Exercise training, especially high intensity interval training, enhanced the machinery (ribosomes) to produce proteins, increased the production of proteins and enhanced protein abundance in muscle," Nair said. He said the results also showed that "the substantial increase in mitochondrial function that occurred, especially in the older people, is due to increase in protein abundance of muscle."

In some cases, the high-intensity regimen actually seemed to reverse the age-related decline in both mitochondrial function and muscle-building proteins.

Exercise's ability to transform mitochondria could explain why it benefits our health in so many different ways, according to the authors. Muscle cells, like brain and heart cells, are unusual in that they divide only rarely compared with most cells in the body. Because muscle, brain and heart cells do wear out yet are not easily replaced, the function of all three of these tissues are known to decline with age, noted Nair.

If exercise restores or prevents deterioration of mitochondria and ribosomes in muscle cells, exercise possibly performs the same magic in other tissues, too. And, although it is important simply to understand how exercise impacts the mechanics of cells, these insights may also allow researchers "to develop targeted drugs to achieve some of the benefits that we derive from the exercise in people who cannot exercise," Nair said.

"We cannot have enough studies surrounding this information because of how impactful it is for health," said Trilk, who was not involved in the research. She explained that if younger people boost mitochondrial function when they're young, they would be preventing disease, while for an older population, they would also be preventing disease while maintaining skeletal muscle, which wanes in older age.

"Mitochondrial function is important to almost every cell in the human body," Trilk said. "So when you don't have mitochondrial function or when you have mitochondrial dysfunction, you have dysfunction of cells, so from a molecular standpoint, you start seeing cellular dysfunction years before you start seeing the global effect, which ends up coming out as symptoms of diseases: diabetes, cancers and cardiovascular disease."

"A strength is that they studied males and females," Zierath said, though she noted that the number of participants in each group was "quite small." Still, this is a minor flaw.

"It teases out some of the training regimes that might be leading to greater effects on what they call mitochondrial fitness," she said. Compared with the other two exercise programs, interval training "really had a more robust effect" on the machinery of cells, she said.

"It boosted the proteins that are important for mitochondrial function -- the oxygen powerhouse of the cells," Zierath said. "It reversed many of what we call age-related differences in mitochondrial function and oxidative metabolism."

"Part of what happens with HIIT is, you disturb homeostasis, you exercise at a really high level, and the body needs to cope with that," she explained.

Even though one program had superior effects, "every single exercise protocol they tested had positive effects," said Zierath, who is looking forward to future research in this vein.

"We need to understand even more about how the human body adapts to different exercise regimes and how this can be important for mitigating what we see as sort of aging-related changes that occur in the functionality of muscle and the ability of the muscle to metabolize fuel, sugar and fat," she said.

"Exercise is almost a medicine in some respects," Zierath said. "It's never too late to start exercising."

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Partnership Formed to Advance Bioelectronic Medicine and Cell Therapy – Pharmaceutical Processing

Northwell Health and United Therapeutics announce strategic partnership.

Northwell Health's Feinstein Institute for Medical Research and United Therapeutics Corporation announced today a strategic partnership focused on the application of bioelectronic medicine and cell therapy to cardiology, hypertension and post-transplant tolerance induction.

"We are truly honored to work with the pioneers of these next generation medical technologies," said Martine Rothblatt, PhD, United Therapeutics' Chairman and Chief Executive Officer. "We expect a great fit with our clinical development pipeline in heart failure, pulmonary disease and transplantation."

"Collaboration is the indispensable factor in successful medical research," said Kevin J. Tracey, MD, President and CEO of the Feinstein Institute. "With great partners, you can accomplish great things for science and for patients. United Therapeutics is such a partner, we share their aims and their values, and we could not be more pleased than to join with them in this effort.

Under the strategic partnership, United Therapeutics will fund Northwell's efforts in four research and development tracks, while United Therapeutics will bring the results into clinical development. The two organizations are working toward the goal of initial regulatory approvals within five years.

Two of the research projects will be conducted by the Feinstein Institute's Center for Bioelectronic Medicine (CBEM). The Feinstein Institute is a worldwide leader for the advancement of scientific knowledge and intellectual property for the rapidly emerging field of bioelectronic medicine.

Bioelectronic medicine represents the convergence of three well-established scientific fields: neuroscience, molecular and cell biology, and bioengineering. The Feinstein Institute team, led by Dr. Tracey, a neurosurgeon who pioneered the field, has been working in this area since 1998, and Northwell Health has already invested $75 million in support of the underlying research. As bioelectronic solutions are successfully identified, tested and refined, CBEM will foster the creation of new companies to bring life-changing solutions to market.

United Therapeutics Corporation is a biotechnology company focused on the development and commercialization of products to address the unmet medical needs of patients with chronic and life-threatening conditions.Northwell Health is New York State's largest health care provider with 21 hospitals and over 550 outpatient facilities.The Feinstein Institute for Medical Research is the research arm of Northwell Health.

(Source: EurekAlert!)

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Partnership Formed to Advance Bioelectronic Medicine and Cell Therapy - Pharmaceutical Processing