News and Events
The February 2019 edition of the Michigan Medicine-PUHSC JI News is now available. The latest edition includes a 2018 Symposium recap and scheduling information for 2019; a profile of a new JI project from co-PIs Robert Dickson and Ning Shen; a look at a prestigious National Center for International Research for PKUHSC; and much more.
The Michigan Medicine-Peking University Health Science Center Joint Institute (JI) for Translational and Clinical Research is now accepting proposals from investigators working collaboratively at both institutions for funding of projects that will demonstrate an effective team approach to discovery and new findings on diseases relative to both countries, and which can be leveraged for extramural funding opportunities.
Funding amount and eligibility
Discovery awards are available (up to $100,000/year for two years) for new, early-stage collaborations. Larger Pilot awards (up to $300,000/year for two years) will support projects between investigators with an established track record of collaboration. New in 2019, the JI leadership is pleased to extend this funding opportunity to faculty from all health science disciplines (note that some cost-sharing is excepted from schools outside Michigan Medicine to obtain matching support from U-M).
Letters of Intent (LOI) due: Feb. 22, 2019
Notifications to submit full proposal and application: March 4, 2019
Full submissions due: May 1, 2019
Notice of award: September 2019
Nearly 100 of China’s top physician researchers recently visited Ann Arbor for a meeting highlighting collaborations between Michigan Medicine and Peking University Health Science Center (PKUHSC), in Beijing.
This year’s Joint Institute (JI) Symposium brought PKUHSC faculty in disciplines from cardiology and liver disease to mental health and big data. The three-day meeting took place Oct. 15-17 across the U-M medical campus and included sessions on cancer research, medical education, addiction, dental health, and more, as well as time for individual collaborators to advance dozens of ongoing JI projects. The JI is the medical school’s largest single international partnership.
“Our ability to reach out beyond our own institutions – and beyond our own borders – is vitally important. As our world gets smaller, the inverse is true of our problems. They get bigger and more complex,” said U-M President Mark Schlissel in his welcome address to open the meeting. “Together, we understand that global challenges demand collaborations that bring together some of the best minds in the world to think big and tackle problems that transcend language, culture and politics.”
Launched 2010, the JI is co-funded by Michigan Medicine and PKUHSC and offers seed grants to teams of investigators between the institutions to collaborate on mutually beneficial projects in a variety of disciplines. Since its inception, the JI has funded nearly 50 projects in cardiology, nephrology, pulmonary care, fertility, and more, research that has garnered 60-plus high-impact publications and more than $14 million in external funding to date.
Recent expansions have included more projects in areas such as emergency medicine, psychiatry and mental health, precision medicine, and medical education. There were ten new awards this year, the largest cohort yet. A recently established JI Leadership & Development Council, headed by Michigan Medicine Victors campaign chair Richard Rogel and Beijing hospital owner Lana Hu, is also poised to grow the collaboration.
“It’s gratifying to think about how far we’ve come. In eight short years, the JI has become a model for how institutions can sustain meaningful collaborations through common goals, shared values, and mutual respect,” said JI co-director Joseph Kolars, UMMS Senior Associate Dean for Education and Global Initiatives, who helped launch the partnership shortly after joining Michigan Medicine. “I’m grateful to my colleagues at PKUHSC and to the dedicated faculty on both sides who continue to advance this important partnership.”
While PKUHSC has many partnerships abroad, the relationship with Michigan Medicine is the longest-running and largest. Thanks in large part to the success of the JI, PKUHSC was recently recognized by the Chinese government with a National Key Center designation for international research collaborations, an honor that elevates the partnership’s status across China and could result in increased funding opportunities for participating researchers.
Kolars co-directs the JI with PKUHSC Vice President Ning Zhang, PhD. Zhang, a Johns Hopkins-trained molecular biologist, who recently joined the faculty at PKUHSC. This year’s JI Symposium marked Zhang’s first.
“I am very enthusiastic about the research programs I’ve seen here (at UMMS) and excited about the JI partnership. While we have many international partnerships, the JI is our top priority,” he said. “We’ve never organized a program like it with any school before. Our leadership is engaged. More important, our faculty are very excited about this collaboration.”
Ten new research projects have been selected for the most recent round of funding through the University of Michigan Health System’s Joint Institute partnership with Peking University Health Science Center.
This year’s cohort of new projects represents largest since the Joint Institute was formed eight years ago. The projects, each co-led by a UMMS faculty member and their PUHSC partner, span a number of areas, from exploring the genetic causes of intellectual disabilities to studying whether and how risk complications from diabetes differ between the U.S. and Chinese populations. Congratulations to the following grant recipients!
Identification of Tumoricidal T Cell Receptors from Hepatocellular Carcinoma-infiltrating CD8+ T Lymphocytes
UMMS: Clifford Cho, MD, FACS
PKUHSC: Yuan Hong, MD, PhD
Hepatocellular carcinoma (HCC) is an aggressive malignancy whose poor prognosis is driven in part by a lack of curative treatment options. We previously cloned three novel HCC-specific murine T cell receptor (TCR) genes that can redirect human T cells to effectively eliminate HCC tumor cells, demonstrating the potential to engineer a patient’s autologous T cells to treat HCC. In addition, we have isolated specific CD8+ tumor infiltrating lymphocytes (TILs) from HCC patients and observed their potent antitumor function after in vitro proliferation. In this project, we seek to infuse CD8+ TILs derived from HCC patients into immunodeficient mice harboring autologous HCC, and subsequently clone TCR genes from patient-derived CD8+ T cells with antitumor phenotype. Following validation of their functions, we will determine their targeted tumor antigens through epitope prediction algorithms and unbiased screening using yeast-display libraries. In sum, we will identify novel tumoricidal TCR genes from HCC CD8+ TILs, thereby engineering patient-derived autologous T cells to generate potently tumoricidal TCR-T lymphocytes to treat HCC patients.
Therapeutic Implications of Natural Killer Cell Immune Surveillance in Lung Cancer
UMMS: Venkateshwar Keshamouni, PhD
PKUHSC: Jun Wang, MD, PhD
Lung cancer is the leading cause of cancer mortality worldwide. Use of immune-checkpoint blockers has yielded impressive clinical benefit, but only in a subset of patients. Recent studies demonstrate that the expression of the checkpoint-ligands like PDL-1 on host cells, rather than on cancer cells, determines the efficacy of checkpoint-blockade in mice. A number of host immune cells, including NK cells, express PDL-1 and could dictate the efficacy of checkpoint-inhibitors in humans. A recent phase I/II study combining anti-KIR (an inhibitory NK cell receptor) antibody with anti-PD1 antibody in head & neck cancer showed a dramatic 24% objective response rate over 13.3% with anti-PD1 alone. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process by which epithelial cancer cells acquire migratory and invasive capabilities to metastasize. We demonstrated that a 20-gene EMT-signature is predictive of survival in non-small cell lung cancer (NSCLC) patients. More recently, we showed that EMT-induced expression of a cell-adhesion molecule CADM1 renders cancer cells more susceptible to NK cytotoxicity and inhibits metastasis. This proposal will test whether boosting NK cell functions can control metastasis and whether the EMT signature can be predictive of anti-tumor efficacy of NK cell therapy, as well as response to checkpoint-blockade therapy in NSCLC. The study seeks to provide proof-of-principle for a potential phase I/II study for proposed NK cell-based strategies, along with the support to the potential of EMT-signature and NK cell phenotype in predicting response to checkpoint-blockade and pave the way for subsequent mechanistic studies.
Rapid identification of Pathogens in Ventilator-associated Pneumonia Using Real-time Metagenomics and Real-time PCR
UMMS: Robert Dickson, MD
PKUHSC: Ning Shen, MD
Ventilator-associated pneumonia (VAP) is a tremendous cause of morbidity, mortality, and healthcare expense in China and the United States. Clinical identification of respiratory pathogens still relies on the culture-based techniques used by Pasteur in the 1880s. Delayed identification of pathogens in pneumonia results in increased morbidity and mortality, and indiscriminate use of broad empiric antibiotics impedes antimicrobial stewardship. The long-term objective of this proposal is to accelerate the identification and quantification of pathogens in VAP using novel, real-time molecular technologies. We will develop a protocol and pipeline that will rapidly identify respiratory pathogens in four hours via real-time metagenomics. In addition, we will develop a protocol and determine reference ranges that will rapidly quantify respiratory pathogens in two hours using a novel ultrasensitive PCR platform.
Integrative and Trans-ethnic Cutaneous T-cell Lymphoma (CTCL) Study to Reveal Clinical and Molecular Determinants for Disease Prognosis
UMMS: Lam Tsoi, PhD & Trilokraj Tejasvi, MBBS, MD
PKUHSC: Yang Wang, MD
Cutaneous T-cell lymphoma (CTCL) is a major form of the primary cutaneous lymphomas and affects all populations in the world including the American and Chinese. CTCL symptoms range from mild itchy red patches to large, painful, disfiguring, cerated nodules, and patients with the advanced stages of CTCL only have up to a 50% three-year survival rate. CTCL patients respond differently to current available treatments, and the subtypes (e.g., Sézary syndrome) vary greatly in their relapse-rate and prognosis. While we and others have conducted population-specific genetic, epidemiological, and/or molecular studies, there has not been any cross-ethnic study to systematically evaluate the shared/unique risk factors associated with prognosis cross populations. With CTCL being an uncommon cancer with limited armamentarium in management, it is imminent to identify robust prognosis biomarkers. This project will set forth the first collaboration between the UMHS Department of Dermatology and the PUHSC Department of Dermatology, as well as Venereology from the Peking University First Hospital, drawing on the unique resources and the expertise of the investigators from the two institutions.
β-adrenergic Receptor Activation in Cardiac Injury and Atherosclerotic Plaque Stability: Role of NPDPH Oxidase 4 (NOX4)
UMMS: Marschall Runge, MD, PhD
PKUHSC: Youyi Zhang, MD, PhD
Cardiovascular disease (CVD) is the leading cause of death worldwide, representing 31% of all deaths. Emerging evidence suggests that stress in adulthood acts as a disease trigger in individuals with high atherosclerotic burden and is a determinant of prognosis and clinical outcomes. Increases in cardiovascular events were reported immediately after traumatic events such as natural disasters, war, and terrorist attacks of 9-11. Although the link between various stressors and disease end points is obvious, much less is known how the pathophysiological mechanisms through which stress responses transform into changes that initiate the development and progression of CVD. Another challenge is addressing the stressors by intervention, because such events are stochastic and therefore difficult to predict. We propose to elucidate the molecular signaling pathways which regulate the transformation of stress responses into cardiovascular events in people with atherosclerotic burden using mouse models of oxidative stress available in the Runge laboratory. These studies will establish the role of NOX4 NADPH oxidase in cardiovascular events in the backdrop of high atherosclerotic burden and potentially identify strategies that work in concert with standard of care treatment for the prevention of cardiovascular events under stress conditions.
Targeting Tumor Neoantigen-specific Tumor Infiltrating Lymphocytes in Non-small Cell Lung Cancer
UMMS: Andrew Chang, MD
PKU Shenzhen Hospital: Jixian Liu, MD
Tumor infiltrating lymphocytes (TILs) comprise a subset of white blood cells isolated from the tumor and surrounding parenchyma that are thought to mediate tumor-specific immune responses. Autologous TIL cultures, isolated from resected tumor tissue, expanded ex vivo and subsequently reinfused into the preconditioned donor patient, have been shown to elicit durable response rates with some instances of long-term survival. In contrast, another subset of TILs appears to attenuate clinical response. We hypothesize that TILs which recognize tumor-specific neoantigens originate from somatic mutations and are more effective in eliciting a clinically significant response. As proof of concept, it has been shown that TILs harvested from resected metastatic lung tumors from a subject with metastatic colorectal carcinoma recognized neoantigens generated by the mutant KRAS-G12D. Re-infusion of expanded TILs led to a significant antitumor response in this subject. The aim of our study is to utilize high throughput sequencing and tetramer flow cytometry to identify tumor-specific neoantigens derived from patients with non-small cell lung carcinoma, both adenocarcinomas and squamous cell carcinomas, as a prelude to the treatment of NSCLC patients with autologous T cells.
Understanding the Heterogeneity in the Risk of Diabetes Complications in China and the US
UMMS: Rodica Pop-Busui, PhD
PKUHSC: Lixia Zhang, MD, MPH
The global trend towards obesity, physical inactivity and energy-dense diets has led to a rapid rise in the prevalence of diabetes. It is estimated that 415 million people live with diabetes, with a projected increase to 642 million by 2040. Practical and cost-effective interventions at national levels are essential to attenuate the global burden of diabetes. Current evidence have shown that glucose control designed to achieve near-normal glycemia may reduce the risk of chronic complications in patients with type 1 diabetes (T1D) and some patients with type 2 diabetes (T2D). However, a critical knowledge gap remains in understanding what persons with diabetes do or do not develop complications, independently of glucose control, and whether there are populations and regions-specific differences in this risk. We hypothesize that populations from different ethnic origin/regions express diverse specific phenotypes of diabetes and its complications and hope to identify mechanism-based therapies for the treatment of diabetes complications so treatment can be individualized and targeted appropriately.
Inflammatory Mediators of Cardiac and Other End Organ Dysfunction During Venoarterial Extra-corporeal Membrane Oxygenation
UMMS: Paul Tang, MD, PhD
PKUHSC: Feng Wan, MD
Cardiovascular disease is the leading cause of death in the world. The use of extracorporeal membrane oxygenation (ECMO) for the treatment of cardiopulmonary collapse has risen exponentially. Data show that 86,287 cases of extracorporeal membrane oxygenation were performed in 2017. Of these 10,982 cases were performed for cardiogenic shock. Thus, the complications and morbidities of ECMO has an enormous impact on resource utilization as well as patient outcomes. A major complication that impairs patient survival is the impairment of end organ function associated with ECMO-induced inflammation. Furthermore, this inflammation can impact myocardial recovery and predict right heart failure after bridge of ECMO to a left ventricular assist device (LVAD). Right ventricular failure after LVAD implant is also a predictor of prolonged hospitalization as well as increased patient morbidity and mortality. Our objective is to determine the association of ECMO mediated inflammation with end organ dysfunction including impairment of myocardial function. Distinct from previous studies, this investigation will focus on patients undergoing venoarterial ECMO for cardiogenic shock either in the setting of acute cardiac decompensation or failure to wean from cardiopulmonary bypass after cardiac surgery.
Identification and Establishment of Novel Pathogenic Genes Involved in Intellectual Disability/ Developmental Delay with Hypomyelinating Leukodystrophy in China
UMMS: Margit Burmeister, PhD
PKUHSC: Jimgmin Wang, PhD
Intellectual disability/development delay (ID/DD) is a common group of neurodevelopmental disorders characterized by substantial limitations in both intellectual functioning and adaptive behavior, starting before the age of 18 years with a prevalence of 1%~3%. Genetics is known to have an important role in etiology of ID/DD. Discerning the precise genetic causes for specific ID/DD patients will inform prognosis, management and therapy, enables access to disorder-specific support groups, and facilitates family planning. Specific knowledge of the genetic basis of disease may in some cases also lead to direct therapeutic interventions. Trio-based whole exome sequencing (WES) has become the best option to identify genetic causes of ID/DD. Although rare variants in more of >700 different genes have now been shown to be associated with ID/DD, many disease-causing genes still remain to be discovered. Building on prior collaborations, we aim to identify and further study genetic causes of ID/DD&HLD patients. Establishing neuronal cell lines for promising candidate gene variants will provide a cellar platform for pathogenesis studies and in-vitro drug screens.
Systematic Investigation of the Microbiome-host Interactions in H. pylori-associated Gastric Cancer Patients
UMMS: Yongqun He, PhD
PKUHSC: Jianmin Wu
Gastric cancer is the fifth most prevalent malignancy and the third leading cause of cancer death worldwide. Almost a half of new cases of gastric cancer occurred in China, where it is the second leading cause of cancer death. The strongest risk factor for gastric cancer is chronic Helicobacter pylori infection. People with H. pylori infection have a roughly six-fold greater risk of developing gastric cancer than uninfected people. However, not all people infected with H. pylori will develop gastric cancer, suggesting more factors and mechanisms involved in gastric carcinogenesis. We hypothesize that complex interactions between host genetic susceptible factors, H. pylori, and other gut microbes influence the host molecular and cellular activities, leading to the development of gastric cancer. Our study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis, with ex vivo verification using organoid models. This systematic study will identify candidate synergistic factors with H. pylori in gastric carcinogenesis and provide proof-of-concept ex vivo experimental verification using organoid models, leading to further understanding of gastric carcinogenesis.
The 2018 JI Symposium promises to be the largest yet, with some 90 participants from PUHSC and many more from Michigan Medicine attending. But for those who can’t make it in person, large portions of this year’s meeting will be streamed online.
The event takes place Oct. 15-17 at Michigan Medicine, with most full-group session activities being held Oct. 16 and 17 in the Biomedical Science Research Building (BSRB) Kahn Auditorium. Nearly all of the full-session portions of the program, including the plenary speeches, panel discussions, and JI project presentations, will be available for live viewing via BlueJeans, Michigan Medicine’s video conferencing partner. In addition to watching, those logging in will have the ability to actively participate through a moderated chat-room session. Online participants will be able to pose a question or make a comment to the presenters in real time.
To join from a web browser click here.
In addition to a schedule and preview of the upcoming Symposium, the September 2018 edition of the JI Newsletter features a look at the newly awarded JI projects, profiles a PKUHSC visitor to Ann Arbor, and looks back on the recent U-M China Biomedical Conference for Chinese alumni of UMMS. Download the Newsletter here.
A new dual degree initiative between the Bioinformatics departments at the University of Michigan Medical School and Peking University Health Science Center (PUHSC) is set to launch next year.
|PUHSC Dean of Basic Sciences Yuxin Yin (left), led a recent delegation to Michigan Medicine in May to finalize plans for a new dual degree program in Bioinformatics.|
The program will bring top graduate students from China to Ann Arbor starting in the fall of 2019. Participants will split their time between U-M and the PUHSC campus in Beijing, earning a master’s degree from each institution. The initiative marks a meaningful expansion of the ongoing partnership between the two medical schools, collaborations that are administered through the UMMS-PUHSC Joint Institute for Translational and Clinical Research.
“This is taking a successful research platform and adding an education component, which will only serve to make the partnership stronger,” said UMMS Professor of Bioinformatics Margit Burmeister, PhD, who has long had partnerships in China and is helping to shape the new dual degree program.
“Big data is a good area to focus on because it is such a growth field. In China, they have strong traditional disciplines – medicine, engineering, computer science. But bioinformatics is about putting those individual disciplines together into a meaningful degree program, something we at U-M have a lot of experience in,” Burmeister said.
A leadership group from PUHSC visited Ann Arbor earlier this month to work through the program details with UMMS Joint Institute leaders and leaders from the Bioinformatics department. UMMS is set to take 4-5 students the first year, with an opportunity for program expansion down the road. In the course of three years, combining coursework and research, participants will earn a master’s in science from PUHSC and a master’s in bioinformatics from U-M.
|Implementing the dual degree program for Michigan Medicine are Bioinformatics Chair Brian Athey (left) and Professor of Bioinformatics Margit Burmeister.|
Bioinformatics uses computers to sort, analyze, and interpret the huge genomic datasets that are increasingly prevalent in precision healthcare. Michigan Medicine has one of the United States’ largest and most well established bioinformatics programs. PUHSC recently launched its own, and students are seeking any advantage to establish themselves in the relatively nascent field.
The new dual degree initiative with PUHSC follows a similar partnership with the Chinese University of Hong Kong, Shenzhen which will bring students from that campus to Ann Arbor to study bioinformatics beginning next year as well. In that case, the students will get an accelerated undergraduate degree from their home university and a master’s from UMMS.“Bioinformatics is growing so fast in China that many students want a master’s degree and then they want to begin their career. If a student is able to get a degree from both PUHSC and UM, that will set them apart,” said Yuxin Yin, MD, PhD, Dean of Basic Sciences and Director of the Institute of Systems Biomedicine at PUHSC. “There is a lot of interest in this program among our students.”
Such international partnerships benefit the UMMS bioinformatics program in the short-term and long-term, said Brian Athey, the Michael Savageau Collegiate Professor and Chair of Computational Medicine and Bioinformatics.
“I’m very enthused about this partnership, including the possibility of expanding to get some of our students in China, too,” said Professor Athey. “Without question, China is the place where biotechnology is having the biggest growth and attracting the most investment currently, so being able to offer our students the opportunity to learn about what’s happening and make connections there is vital.”
|JI researchers Robert Brook, UMMS Professor of Cardiology (right), and UMMS Research Associate Robert Bard (left) visit the lab of Wei Huang, Peking University Professor of Public Health.|
Short-term exposure to high levels of air pollution can cause elevated blood pressure even in healthy adults, according to a newly published paper by Joint Institute researchers.
Michigan Medicine Professor of Cardiology Robert Brook and his partner, Research Professor Wei Huang at the Peking University Health Science Center (PUHSC) School of Public Health, have been studying how air pollution impacts cardiovascular function in both Beijing and Ann Arbor. Their recent publication in the American Journal of Hypertension marked the first research of its kind to harmonize studies of healthy people in Beijing, where air pollution levels are typically high, against counterparts in southeast Michigan, with comparatively clean air.
“We’ve done international studies before and seen blood pressure-raising effects of air pollution in both Beijing and in Ann Arbor, but they were done with participants who are already at higher risk factors for cardiovascular disease,” said Brook, MD. “We’d never really done a comparative study with completely healthy people like this.”
Participants wore a small device to monitor air pollution levels for a 24-hour period before reporting to the clinic, where researchers took their blood pressure and gathered other biometric information. They repeated this process multiple times. The air quality data from their wearable monitors, supplemented with regional monitors in both locations, allowed the researchers to see if and how exposure to varying levels of pollution impacted blood pressure. In Michigan, there was no appreciable impact. Not so in Beijing, where the outdoor air pollution levels during the testing period were higher by factor of nearly 10.
“Even if you’re a healthy person living in Beijing, the pollution will still impact your blood pressure. The effect is typical of what we would expect to see if someone’s weight changed by five or ten pounds,” said Brook. “That kind of increase, while relatively modest at the individual level, cumulatively translates to a very large public health risk when you extrapolate across a city like Beijing of more than 20 million people.”
A forthcoming paper in the American Journal of Cardiology (in press) demonstrates the negative impacts Brook and Huang saw on HDL particle function in healthy subjects, and the team has garnered external funding for a future study exploring the effectiveness of face masks and indoor air filters in China.
“We now have a grant to study the effectiveness of face masks and indoor air filters for people with coronary artery disease,” Brook said. “This has been a phenomenal partnership. The best thing that’s happened has been forging collaborations with like-minded colleagues in cardiology and public health at PUHSC. The relationships have been really rewarding and have opened new doors for me.”
The newest edition of JI News features information about a new dual-degree program in Bioinformatics expected to bring students from PUHSC to study in Ann Arbor beginning next year. Read about Drs. Robert Brook and Wei Huang's work exploring the impacts of air pollution on cardiovascular function in populations in the U.S. and Beijing. Peking University People’s Hospital Attending Doctor Jing Zhou discusses his experience to date as a visiting research scholar at Michigan Medicine, and UMMS resident Mark Kluk makes time for some research during his clinical elective at Peking University First Hospital. Download the latest issue here.