Extracellular Matrix Archives - Sanford Burnham Prebys

Eva Engvall earned her PhD from the University of Stockholm in 1975. Her postdoctoral work was done at the University of Helsinki and City of Hope National Medical Center in California, where she was subsequently appointed to staff. Dr. Engvall was recruited to Sanford-Burnham Medical Research Institute in 1979. For 1994-1996, Dr. Engvall held joint appointments at this institute and as Chairperson of the Department of Developmental Biology at Stockholm University. Dr. Engvall’s work on the development of the Enzyme Linked Immunosorbent Assay, ELISA, has been widely acclaimed, including honors from The German Society for Clinical Chemistry, the U.S. Clinical Ligand Assay Society, and in 1995, a special award from the Ed and Mary Shea Family Foundation. Dr. Engvall received an honorary degree in Medicine from the University of Copenhagen in November 1994.

Related Disease
Muscular Dystrophy

Phenomena or Processes
Extracellular Matrix

My Story

I came to the Institute, then the La Jolla Cancer Research Foundation, in 1979. The Institute allowed me total freedom to pursue my research without any interference or bureaucracy. If I could get grants from the NIH, I could do whatever I wanted.

My interest was the extracellular matrix and cell-matrix interactions. Using the relatively new technology of monoclonal antibodies, I decided to find out if the extracellular matrix was different in different tissues (not known at the time). We identified and characterized some of the selectively expressed proteins. One of those is “merosin”, a member of the laminin family that is only present in the basement membranes of muscle and nerve. We predicted that defects in merosin would result in muscle and/or nerve disease. Indeed, we found that defects in merosin are the cause of the second most common form of muscular dystrophy. Lynn Sakai, at the Portland Shriners Research Center and Professor of Biochemistry & Molecular Biology, OHSU, and I discovered another extracellular matrix protein with unique distribution, fibrillin, and fibrillin is mutated in Marfan syndrome.

My assays and antibodies have been extensively used all over the world both in research and in human and veterinary medical diagnosis.

Other than my own laboratory research, I shared the interest of Lil Fishman, one of the founders of the Institute, in the mentoring of young scientists. Lil and I did this together in many ways: lunches for new postdocs, a monthly newsletter, courses on different scientific topics, and lectures by famous local scientists on how to succeed in science. I have been a member of the Fishman Fund advisory board and a reviewer of applications for the annual Fishman Fund Award for postdoctoral fellows.

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Showing 3 of 3

Enzyme immunoassay ELISA and EMIT.

Engvall E

Methods Enzymol 1980 ;70(A):419-39

Basement membrane diversity detected by monoclonal antibodies.

Hessle H, Sakai LY, Hollister DW, Burgeson RE, Engvall E

Differentiation 1984 ;26(1):49-54

Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils.

Sakai LY, Keene DR, Engvall E

J Cell Biol 1986 Dec ;103(6 Pt 1):2499-509

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Dr. Yu Xin (Will) Wang received his PhD at the University of Ottawa where he identified cellular asymmetry and polarity mechanisms regulating muscle stem cell self-renewal and skeletal muscle regeneration. He then carried out postdoctoral training at Stanford University School of Medicine developing single cell multi-omic approaches to characterize the regenerative process and what goes awry with disease and aging.

“I’ve always had a passion for science and became fascinated with how the body repairs and heals itself when I was introduced to the potential of stem cells in regenerative medicine. I was struck by the ability of a small pool of muscle stem cells that can rebuild and restore the function of muscle. My lab at Sanford Burnham Prebys aims to better understanding the repair process and harness our body’s ability to heal in order to combat chronic diseases and even counteract aging.”

Education and Training

Postdoctoral Fellowship, Stanford University School of Medicine
PhD in Cellular Molecular Medicine, University of Ottawa, Canada
BS in Biomedical Sciences, University of Ottawa, Canada

Prestigious Funding Awards

2020: NINDS K99/R00 Pathway to Independence Award

Honors and Recognition

Governor General’s Gold Medal – Canada

Related Disease
Aging-Related Diseases, Amyotrophic Lateral Sclerosis (Lou Gehrig’s Disease), Arthritis, Cachexia, Inflammatory/Autoimmune Disease, Multiple Sclerosis, Muscular Dystrophy, Myopathy, Neurodegenerative and Neuromuscular Diseases, Sarcopenia/Aging-Related Muscle Atrophy, Spinal Muscular Atrophy

Phenomena or Processes
Adult/Multipotent Stem Cells, Aging, Cell Signaling, Development and Differentiation, Epigenetics, Exercise, Extracellular Matrix, Neurogenesis, Organogenesis, Regenerative Biology, Transcriptional Regulation

Anatomical Systems and Sites
Immune System and Inflammation, Musculoskeletal System, Nervous System

Research Models
Clinical and Transitional Research, Computational Modeling, Human Adult/Somatic Stem Cells, Mouse

Techniques and Technologies
3D Image Analysis, Bioinformatics, Cellular and Molecular Imaging, Gene Knockout (Complete and Conditional), Genomics, High Content Imaging, High-Throughput/Robotic Screening, Live Cell Imaging, Machine Learning, Microscopy and Imaging, Proteomics, Transplantation

The Wang lab is interested in elucidating critical cell-cell interactions that mediate the function of tissue-specific stem cells during regeneration and disease, with a focus on

how a coordinated immune response can promote regeneration and
how autoimmunity impacts tissue function and hinder repair.

Specifically, the Wang lab aims to identify cellular and molecular crosstalk between muscle, nerve, and immune systems to develop targeted therapies that overcome autoimmune neuromuscular disorders and autoimmune aspects of “inflammaging.”

Yu Xin (Will) Wang’s Research Report

The lab’s research is translationally oriented and utilizes interdisciplinary molecular, genetic, computational (machine learning and neural networks), and bioengineering approaches to view biology and disease from new perspectives. We combine multi-omics sequencing and imaging methods to resolve how different cell types work together after injury to repair tissues and restore function. We use a data-driven approach to identify targetable disease mechanisms and, through collaborations with other researchers and clinicians, develop therapies that promote regeneration. Visit our lab website to learn more.

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Showing 3 of 3

Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength.

Palla AR, Ravichandran M, Wang YX, Alexandrova L, Yang AV, Kraft P, Holbrook CA, Schürch CM, Ho ATV, Blau HM

Science 2021 Jan 29 ;371(6528):

EGFR-Aurka Signaling Rescues Polarity and Regeneration Defects in Dystrophin-Deficient Muscle Stem Cells by Increasing Asymmetric Divisions.

Wang YX, Feige P, Brun CE, Hekmatnejad B, Dumont NA, Renaud JM, Faulkes S, Guindon DE, Rudnicki MA

Cell Stem Cell 2019 Mar 7 ;24(3):419-432.e6

Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division.

Dumont NA, Wang YX, von Maltzahn J, Pasut A, Bentzinger CF, Brun CE, Rudnicki MA

Nat Med 2015 Dec ;21(12):1455-63

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Phenomena or Processes
Actin Cytoskeleton, Adipocyte Differentiation, Aging, Apoptosis and Cell Death, Cancer Biology, Cancer Metabolism, Cancer-Associated Glycans, Cell Adhesion and Migration, Cell Differentiation, Cell Signaling, Combinatorial Therapies, Damage-Associated Molecular Patterns, Extracellular Matrix, Glycosylation, Inflammation, Innate Immunity, Integrins, Metabolic Networks, Mitochondrial Biology, Organic/Synthetic/Medicinal Chemistry, Tumor Microenvironment, Tumorigenesis

Anatomical Systems and Sites
Adipose Tissue, General Cell Biology, Immune System and Inflammation, Mammary Gland, Vasculature

Research Models
C. elegans, Human, Human Cell Lines, Mouse, Mouse Cell Lines, Primary Cells

Google Scholar profile

After a successful teaching career at the University of Michigan I have had the privilege to “reboot” my research career at Sanford Burnham Prebys where I have had the opportunity to develop novel methodologies to understand cardiomyopathy. I have also had the opportunity to work with NASA scientists to do experiments on the International Space Station.

Education

Postdoctoral Fellow, Stanford University, Palo Alto, CA, Neurochemistry
Postdoctoral Fellow, University of Texas Medical School, Houston, TX, Neuroscience NIMH
PhD, Wesleyan University, Middletown, CT, Neuroscience NIMH
B.A., Lehigh University, Bethlehem, PA, Biology

Prestigious Runding Awards or Major Collaborative Grants

2015-2020: NIH R01 HL132241-01A1 – Using Drosophila genetics to identify molecular links between ion channel dysfunction and pathological cardiac remodeling. (PI) 2013-2018 NASA NRA #NNH12ZTT001N – The effects of microgravity on cardiac function, structure and gene expression using the Drosophila model. (Co-I)

Honor and Awards

2014: Space Florida International Space Station Research Competition Winner – Co-investigator – One of three Basic Research proposals selected for launch aboard SpaceX3 – Mission completed, live flies returned on May 18,2014
2001: Excellence in Teaching Award, University of Michigan
1997: Excellence in Teaching Award, University of Michigan
1986-1988: National Institute of Mental Health Fellowship
1983-1985: National Institute of Mental Health Fellowship
1981: Sigma Xi Research Award 1980 MBL Scholarship, Neural Systems and Behavior Course
1971-1975: National Merit Scholarship, Lehigh University

Board Appointments

2018-present: Board member American Society for Gravitational and Space Research

Related Disease
Aging, Aging-Related Diseases, Atrial Fibrillation, Cardiac Fibrosis, Cardiomyopathies, Heart Disease, Metabolic Syndrome, Molecular Biology

Phenomena or Processes
Actin Cytoskeleton, Calcium Signaling, Cardiovascular Biology, Cell Signaling, Extracellular Matrix, Fuel Metabolism, Integrins, Metabolic Networks, Phosphorylation, Stress Response Pathways

Anatomical Systems and Sites
Cardiovascular System, Heart

Research Models
Drosophila, Larval Zebrafish Heart, Zebrafish

Techniques and Technologies
Biophysiology, Cellular and Molecular Imaging, Fluorescence Microscopy, Gene Silencing, Genetics, In vivo Modeling, Ion Channels, Live Imaging, Microarrays, Microscopy and Imaging, Molecular Genetics, RNA Interference (RNAi), Semi-automated Optical Heartbeat Analysis (SOHA), Systems Biology, Transgenic Organisms

The Ocorr Lab is investigating the cellular and molecular basis of adult heart function and cardiomyopathies using the genetic model system Drosophila.

We use functional, electrophysiological, biochemical and immunohistochemical techniques that allow us to examine the roles of genes and gene products in cardiac channelopathies and stress-related cardiomyopathies.

Our lab pioneered the development of a novel methodology (Semi-automatic Optical Heartbeat Analysis, SOHA) that permits the quantification of heartbeat parameters in model systems with small hearts.

Using this system we have identified several ion channels in the fly heart that play prominent roles in repolarization of the human heart and cause arrhythmia in both the fly and in humans when mutated. We also have developed a number of other disease models including a diabetic-like cardiomyopathy induced by high sugar diet and hypoxia-induced cardiomyopathy.

Recently we have begun collaborations with NASA (by winning a Space Florida International Space Station Research Competition). We are using the fly to uncover the molecular/cellular basis for cardiac and muscle atrophy in astronauts exposed to extended periods of microgravity despite extensive exercise regimes aboard the ISS. Our flies were launched aboard SpaceX 3 for a month-long exposure to micro-gravity.

Karen Ocorr’s Research Report

My lab is working to understand the cellular and molecular basis of heart disease. One project is focused on the genetic basis of Atrial Fibrillation. This project is a collaborative one with the lab of Alexandre Colas. We are combining two model systems, the fly in my lab and human induced cardiomyocytes in his lab, to identify AFib genes that have been implicated from patient studies. Another project focuses on the role of metabolism in cardiomyopathies. This is because obesity and metabolic syndrome are linked to an increased risk of heart disease. We are studying the role of a key metabolic signaling molecule in hypertrophic cardiomyopathy. A separate effort is focused on the role of gravity in heart function. These studies will provide important information for future habitants of colonies on the moon and Mars. But they are also relevant to patients who are bedridden and to patients with muscle wasting (sarcopenia).

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Showing 3 of 3

Prolonged Exposure to Microgravity Reduces Cardiac Contractility and Initiates Remodeling in Drosophila.

Walls S, Diop S, Birse R, Elmen L, Gan Z, Kalvakuri S, Pineda S, Reddy C, Taylor E, Trinh B, Vogler G, Zarndt R, McCulloch A, Lee P, Bhattacharya S, Bodmer R, Ocorr K

Cell Rep 2020 Dec 8 ;33(10):108445

A new method for detection and quantification of heartbeat parameters in Drosophila, zebrafish, and embryonic mouse hearts.

Fink M, Callol-Massot C, Chu A, Ruiz-Lozano P, Izpisua Belmonte JC, Giles W, Bodmer R, Ocorr K

Biotechniques 2009 Feb ;46(2):101-13

Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations.

Ocorr K, Zambon A, Nudell Y, Pineda S, Diop S, Tang M, Akasaka T, Taylor E

PLoS Genet 2017 May ;13(5):e1006786

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After receiving his early training in clinical chemistry/biochemistry at the University of Buenos Aires, Argentina, Dr. Millán first joined the La Jolla Cancer Research Foundation (LJCRF) in 1977, the predecessor of Sanford Burnham Prebys, as a trainee in clinical enzymology. He completed his PhD studies in Medical Biochemistry at the University of Umeå, Sweden and after post-doctoral stints in Copenhagen and LJCRF he was appointed to the faculty at SBP in 1986. He served as Professor of Medical Genetics in the Department of Medical Biosciences at his alma mater, Umeå University, Sweden, from 1995-2000. He was appointed Sanford Investigator at the Sanford Children’s Health Research Center at Sanford Burnham Prebys in 2008.

Honors and Recognition

2018: ASBMR Lawrence G. Raisz Award for Pre-clinical Research.
2001: Gold Medal of the Royal Academy of Medicine and Surgery, Murcia, Spain
1992: Honorary title of AcadémicoCorresponsal at the Royal Academy of Medicine and Surgery, Murcia, Spain.

Other Affiliations

Member, Scientific Advisory Board, Soft Bones

Related Disease
Arthritis, Bone Mineralization Disorders, Cardiovascular Diseases, Colorectal Cancer, Crohn’s Disease (Colitis), Heart Disease, Inherited Disorders, Metabolic Syndrome, Peripheral Vascular Disease, Testicular Cancer

Phenomena or Processes
Cardiovascular Biology, Disease Therapies, Extracellular Matrix, Protein Structure-Function Relationships

Anatomical Systems and Sites
Cardiovascular System, Musculoskeletal System, Vasculature

Research Models
Mouse

The Millán laboratory works on understanding the mechanisms that control normal skeletal and dental mineralization and elucidating the pathophysiological abnormalities that lead to heritable soft bones conditions such as Hypophosphatasia (HPP) and to soft-tissue calcification, including vascular calcification, that is a hallmark in patients affected by a variety of rare genetic diseases as well as in chronic kidney disease. Dr. Millán’s research has already contributed to the implementation of a novel therapy for HPP, a genetic disease caused by deficiency in tissue-nonspecific alkaline phosphatase (TNAP) function, that leads to accumulation in the extracellular space of inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. HPP is characterized by defective mineralization of bones (rickets or osteomalacia), and teeth that display a lack of acellular cementum, hypomineralized dentin and enamel, and periodontal defects. Dr. Millán’s team has demonstrated the effectiveness of enzyme replacement therapy using mineral-targeted recombinant TNAP (asfotase alfa) to prevent the skeletal and dental defects in the TNAP knockout mouse model of infantile HPP. This therapy was approved in 2015 for the treatment of patients with pediatric-onset HPP.

Current efforts, in collaboration with Professor Miyake’s group in Japan (https://www.nms-gt.org/en/members), focus on developing gene therapy as an alternative approach to treat HPP. Dr. Millán’s group has also identified key pathophysiological changes that lead to calcification of the arteries in animal models of generalized arterial calcification of infancy, pseudoxanthoma elasticum and related genetic diseases as well as in animal models of chronic kidney disease. His group, in collaboration with scientists at the Conrad Prebys Center for Chemical Genomics at Sanford Burnham Prebys, has developed proprietary compounds able to ameliorate the soft-tissue calcification in these conditions and clinical trials are now underway using these first-in-class small molecule inhibitors.

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Showing 2 of 2

Visualization of Mineral-Targeted Alkaline Phosphatase Binding to Sites of Calcification In Vivo.

Amadeu de Oliveira F, Narisawa S, Bottini M, Millán JL

J Bone Miner Res 2020 Sep ;35(9):1765-1771

Gene Therapy Using Adeno-Associated Virus Serotype 8 Encoding TNAP-D(10) Improves the Skeletal and Dentoalveolar Phenotypes in Alpl(-/-) Mice.

Kinoshita Y, Mohamed FF, Amadeu de Oliveira F, Narisawa S, Miyake K, Foster BL, Millán JL

J Bone Miner Res 2021 Sep ;36(9):1835-1849

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Phenomena or Process: Extracellular Matrix

My Story

Select Publications

Enzyme immunoassay ELISA and EMIT.

Basement membrane diversity detected by monoclonal antibodies.