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Oct 22, 2018 · Investigative team wins NIDDK grant for Primary Sclerosing Cholangitis research in Primary Sclerosing Cholangitis (PSC)

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A Mayo Clinic-led research consortium recently received a significant, five-year grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to study the pathogenesis and outcomes of Primary Sclerosing Cholangitis (PSC), a chronic, progressive liver disease that lacks effective medical therapy. Dr. Konstantinos Lazaridis, a hepatologist and an established clinician investigator from Mayo Clinic in Rochester, Minnesota, is the Principal Investigator of the study.

Investigative teams at four academic medical centers – Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and University of Oslo, Norway – aim to define the gene-environment interactions driving the disease by using artificial intelligence approaches. In so doing, they will identify molecular disease signatures associated with environmental exposures, metabolism-related chemicals and gut bacteria that are unique to PSC patients. Another goal: integrate and share clinical and experimental data as well as biospecimens generated through the grant-funded research with the broader research community by creating the PSC Scientific Community Resource.

“This is the first translational study of PSC in which we aspire to examine how the interaction of genetic risk along with environmental exposures (i.e., the exposome) leads to development of PSC and its outcomes,” Dr. Lazaridis said. “We are thrilled about this scientific opportunity to better understand PSC and believe the discoveries we make will improve the care of our patients. We are indebted to the study participants for their trust to make this research effort possible.”

To conduct the study and generate the proposed Resource, the team will draw on large, active biorepositories, comprised of patient blood and stool samples. Despite PSC’s rarity – one in 10,000 individuals are diagnosed with the disease – approximately five percent of the entire United States PSC patient population has already consented and provided samples for the planned scientific research.

Since genetics alone could not explain why some people develop PSC and others don’t, the thinking is that casting a broader net via “multi-omics” analysis will help to uncover the complex underpinnings of the disease. Simply put, the investigators will examine and incorporate data from several “omics” layers, specifically the genome (genetics), exposome (environment), metabolome (metabolites), methylome (DNA methylation), transcriptome (gene expression), and metagenome (DNA sequencing of bacteria).

To discover changes in patient blood specific to PSC, the team will test for the presence of environmental exposures – pollutants, pesticides, medications, etc. – and the biological responses corresponding to those exposures. Cutting-edge, ultrahigh resolution mass spectroscopy platforms will be used to evaluate the exposome and metabolome in PSC patients as well as healthy- and disease-controls. Preliminary exposome and metabolome profiling has already revealed chemical exposures and corresponding changes in key liver, lipid metabolism and branched chain amino acid pathways in PSC patients not found in controls. By also identifying DNA methylation patterns, which can change the activity of a DNA segment without changing its sequence, and measuring gene expression levels, researchers will assess “the “methylome” and “transcriptome,” in the hope of uncovering other PSC markers.

Investigators also will assess gut microbial diversity, “the metagenome,” given changes in the types and numbers of helpful and harmful bacteria in the gut are associated with diseases including PSC. They will perform DNA sequencing on the microbes found in stool of patients with PSC, other disease states and healthy controls to get a global overview of processes occurring in the gut. This study will also incorporate a novel exposome-level analysis of stool to elucidate links between microbe classification and exposome-metabolome profiles contributing to PSC.

The resulting, omics-specific datasets will be individually analyzed to identify PSC-associated features, accounting for confounders such as age, sex and genetic variation. Systems biology and high-performance computing expertise will then be leveraged to integrate multiple layers of omics data into a meaningful, multi-omics whole. High-resolution clinical data collected from these patients also will be combined with omics data to shed new light on processes underlying PSC variability in regards to disease onset, features, and outcomes. The hope is to improve predictions of which patients will need liver transplantation, identify biomarkers for PSC-associated malignancy, uncover culprits driving the strong relationship between PSC and inflammatory bowel disease (IBD), as well as reveal differences in the development between childhood and adult PSC.

“Having a better understanding of these clinical priorities holds great promise for a more individualized approach to clinical surveillance and therapy of patients with PSC,” Dr. Lazaridis said.

In total, multi-omics assessments will be generated from over 3,600 individuals, including PSC patients, those with other relevant diseases and healthy-controls. Moreover, the approach – broad patient-based studies and centrally-administered resources upon which new hypothesis can be generated and tested – may serve as a model to inspire new lines of investigation and prioritize clinical trials. The datasets will be accessed by a wide range of investigators, given the fact that PSC is highly associated with IBD as well as bile duct and colon cancers.

“The discovered multi-omics signatures of PSC will provide a springboard for development of novel hypotheses regarding pathogenic mechanisms underlying the disease,” Dr. Lazaridis said. “This is a hypothesis generating grant that could lead to innovative lines of research and hopefully new therapies for this devastating disease.”

Oct 8, 2018 · PSC Physician Scientist Profile: Dr. Konstantinos Lazaridis in Primary Sclerosing Cholangitis (PSC)

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Having trained at the National Human Genome Research Institute (NHGRI) in the early 2000s, Konstantinos N. Lazaridis, M.D., is no stranger to sifting through sequences of human genomes to uncover genetic variants and mutations associated with diseases such as Primary Sclerosing Cholangitis (PSC).

“But to sift for the needle in the hay stack, which is required for making impactful discoveries about disease, you need hundreds, thousands of samples; gathering them is no easy task with a disease as rare as PSC,” Dr. Lazaridis said. Despite the fact that PSC affects only 1 in 10,000 people in the United States, Dr. Lazaridis and his team have collected samples from about 1,500 PSC patients during the past 10 years. The result: about 30,000 tubes of biospecimens with more than a half a million clinical data points collected into a single database representing to our knowledge the largest and most comprehensive PSC biorepository anywhere in the world. And as this effort continues and grows the challenges are changing, including how to maintain and enhance this important resource.

“It has been a humbling experience and a privilege,” Dr. Lazaridis said. “I still remember my emotions when holding in my hands a box containing invaluable individual DNA specimens from the first 100 PSC patients who enrolled in our study from all over the United States, entrusting their genetic blueprint to us. I felt I had in my hands the cause of PSC, and I was wondering how long it would take us and others to crack the mysteries of this disease.”

By examining those blueprints, Dr. Lazaridis and several collaborating groups have now discovered 20 genetic variations associated with development of PSC. Recently in collaboration with industry, the team was able to generate exome sequences of nearly all 20,000 genes comprising each PSC genome in the biorepository. “Each patient and data point have something to tell us about the big picture of this disease,” Dr. Lazaridis said. “So, we have many pieces of a really enormous puzzle to put together.”

Destiny it seems brought Dr. Lazaridis from Greece to Mayo Clinic to figure out that puzzle.

“As a medical student in Greece, I was exposed to many patients with autoimmune hepatitis, and autoimmunity as a disease process was a very intriguing to me,” Dr. Lazaridis explained. “Also, the liver is a resilient organ in charge of several body functions including metabolism and detoxification of substances as well as bile production for digestion.”

Thus, after medical school, his transition to studying the molecular biology of systemic lupus erythematous, an autoimmune disorder that affects many organs including the liver, seemed a natural fit. He secured a two year post-doc position at the University of Texas and the Veterans Administration (VA) Hospital in San Antonio. During that time, Dr. Lazaridis realized he needed specialty training in gastroenterology and hepatology, which the immunologists he was working with couldn’t provide.

In the pre-internet era, to learn which medical center offered the best gastroenterology and hepatology training program, he headed to the VA hospital library. He located a copy of Gastroenterology, the top peer-reviewed journal of the specialty, to find out which institutions the Editor and editorial board hailed from. “At that time, the Editor (Dr. Nicholas LaRusso) and the entire editorial team of Gastroenterology were from Mayo Clinic,” Dr. Lazaridis said. “In the spark of a moment, Mayo Clinic became the goal for my training in gastroenterology and hepatology.”

He applied for a spot in the Internal Medicine training program, but received no word as to whether he was invited for an interview. During the last week of the interviews, he decided to call the office of the program director, three times actually.

“I was busy with experiments that day at the VA and almost forgot to call the program; it was late in the afternoon when I got a free moment,” Dr. Lazaridis said. “After getting no answer the first two calls, I could have stopped, but I persisted and the third time I got Dr. Schultz, the program director himself, on the phone. I explained the situation, and was surprised that he reviewed my application as we were talking and told me that I was an excellent candidate for the program. He offered me an interview a week after the official period.”

The first week of February 1993, Dr. Lazaridis visited Rochester for an interview, and shortly thereafter became an Internal Medicine resident with the good fortune of having Dr. Greg Gores as his advisor. Dr. Gores encouraged him to pursue the Clinician Investigator Training Program and to work with Dr. LaRusso in his laboratory on the molecular mechanisms of cholestasis.

Three years later, Dr. Lazaridis sought to bring his research experience to the patient level, pursuing translational research using human biospecimens. At the suggestion of Drs. Gores and LaRusso, Dr. Lazaridis was given an opportunity for additional research training as a Mayo Clinic Scholar. His mentors suggested he make a choice between studying human genomics or virology of hepatitis C with the goal of establishing an innovative, research program on liver disease in the Division of Gastroenterology and Hepatology.

“I chose the former in a heartbeat,” Dr. Lazaridis said. “This was an easy decision. At that time, the Human Genome Project was well underway and the promise of genomics in medicine was overwhelming.” He interviewed with luminary scientists in the field, Eric Lander, Ph.D., at the Massachusetts Institute of Technology and Francis Collins, M.D., Ph.D., at the NHGRI for the opportunity to join one of the laboratories as a Mayo Clinic Scholar. He was offered a position at both places, and made another key decision.

“I decided to join Dr. Collins’ laboratory because the project that Francis proposed to work on for my training in genomics – dissecting the genetics of type 2 diabetes – could serve as a prototype for what I envisioned developing for cholestatic liver disease,” said Dr. Lazaridis. “I saw the potential of genomics to reveal answers where there were none and opportunities to better understand disease pathogenesis tailored to an individual patient’s genetic blueprint. My two year training at NHGRI was an outstanding experience. Working with Francis changed forever the way I was perceiving mechanisms of disease and taught me the fundamental importance of human disease registries and bio-repositories.”

in 2003, Dr. Lazaridis brought that vision and training back to Mayo Clinic and started his own research program dedicated to dissecting the genetic contributions of rare, progressive, cholestatic liver diseases, such as PSC. “I have immensely benefited from the unparalleled mentoring of Drs. Gores and LaRusso over the past two decades.” Lazaridis said. “They always pointed me in the right direction, yet trusted my decisions and efforts as I was developing a novel program within our Division.”

Today, the primary goal of his research program is to find a cure for and improve the care of patients with PSC. But to find a cure, Dr. Lazaridis emphasizes that the causes of the disease need to be understood. “We believe the development of PSC results from the interaction of environmental exposures and the genetic profile of an individual,” Dr. Lazaridis said.

During the past decade, his team has made significant progress to understand the genetic underpinnings that predispose patients to develop PSC. Through such studies they have determined that genomics alone can’t explain why some people develop PSC and others do not.  Although Dr. Lazaridis began work to elucidate the role of the genome first because scientific tools were available, he’s now turning his attention to studying the role of environmental exposures (“the exposome”) in developing PSC. With the availability of new scientific tools, his team will examine how the interactions of genetic risks and environmental exposures (i.e., toxins and chemicals, etc.) lead to PSC and its complications.

“We are making great progress to unravel the causes of PSC because of patients trust and contribution to our studies, synergy between PSC-focused scientific groups, strong benefactor commitment and funding support from NIH,” Dr. Lazaridis said. “All these forces are coming together to bring an end to this disease…and we will.”

Sep 10, 2018 · Exposomics in PSC Research in Primary Sclerosing Cholangitis (PSC)

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A major goal of our current research for Primary Sclerosing Cholangitis (PSC) involves capturing “the exposome,” or the role of environmental exposures – pollutants, pesticides, medication, diet, etc. – and the associated biological responses to these exposures.

In this video, Mayo Clinic hepatologist, Dr. Konstantinos Lazaridis explains what the exposome is and discusses the significance of this work in elucidating how PSC develops.

Jul 2, 2018 · Mayo Clinic leads biobanking efforts in support of PSC Research in Primary Sclerosing Cholangitis (PSC)

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For more than four decades, the Mayo Clinic Division of Gastroenterology and Hepatology has led the field in clinical and scientific discoveries related to Primary Sclerosing Cholangitis (PSC) and has served as the main referral center for PSC in the United States. As a result, Mayo Clinic is home to the largest PSC biobank in the United States, if not the world. Given the rarity of PSC, the biobank containing biospecimens collected from about 1,500 patients represents a critical resource for translational research studies of the disease.

In the following video, Mayo Clinic hepatologist Konstantinos N. Lazaridis, M.D. explains the importance of this biobank, the effort it took to build it, his team’s immediate and future goals and the privilege of studying such a unique collection of biospecimens.