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Research Division Faculty


 
 

Primary Appointment: Assistant Professor of Pediatrics
Faculty member of the Gates Center for Regenerative Medicine

We are interested in elucidating the underlying mechanisms that lead to the development of diabetes in humans. Diabetes Mellitus is classically divided into type I and type II diabetes. Type I Diabetes (T1D) results from an autoimmune attack that destroys the insulin-producing beta cells, while Type II Diabetes (TIID) has been described as the result of peripheral insulin resistance and the progressive loos of functional beta cell mass. Recent findings indicate that in both conditions, there are subtle defects of the endogenous beta cells that contribute to the development of the diseases. One specific focus of the lab is to investigate and elucidate molecular mechanisms that govern human beta cell development, maturation, replication, function under steady state conditions and response’s to stress(es). While human cadaveric islets can be obtained for research purposes, their availability is limited. In addition, isolated islet preparation quality varies considerably and many confounding factors, including but not limited to age, medical history, isolation procedure, complicate interpretation of experiments, thus requiring large cohort numbers. In the past we have investigated different approaches to generate an abundant source of functional insulin producing beta cells. We were among the first three groups demonstrating the generation of functional beta cells from human pluripotent stem cells under cell culture conditions. These findings have great implications for cell therapy of patients with T1D and first clinical trials are currently conducted by a biotech company using human embryonic stem cell derived pancreatic cells. In addition, to its potential use in treatment of patients, our approach displays tremendous opportunity to study previously inaccessible aspects of human beta cell biology. Pluripotent stem cells have two key features; they divide indefinitely and rapidly, resulting in large numbers of cells and given appropriate clues can differentiate into every cell type of the human body. With the discovery that pluripotent stem cells can be generated from somatic human cells, it is now possible to generate patient specific cell lines with the ability to differentiate into any cell type. Thus enabling us to study beta cell function in a specific genomic context. In addition, we have taken advantage of recent breakthroughs in genome editing technology to establish different inducible CRISPR/Cas9 systems to facilitate rapid and precise gene modification of pluripotent stem- and its differentiated cell derivates. In summary, we have now an abundant and reproducible source of beta cells generated in vitro, that can be precisely manipulated at different levels of gene expression regulation and function.
While the pancreatic beta cell is key to glucose homeostasis, other tissues have critical roles in the development of T1D. On such tissue is the thymus.
The thymus gland is an organ that is essential for adaptive immunity and establishing self-tolerance by providing positive and negative selection of developing T-cells. Hence, failure to efficiently eliminate autoreactive T-cells results in an erroneous immune attack of once own tissue. This is evidently highlighted in patients with mutations in gene`s critical for thymic function, displaying multiple autoimmune conditions. We were the first to demonstrate the successful generation of human embryonic stem cell-derived thymic epithelial cells (TECs) by directed differentiation. TECs supported T cell development upon transplantation in athymic nude mice, indicating their functionality.  Significantly, all our established genome engineering approaches can readily be employed to study human thymic function analog that our approaches for beta cell biology. Hence, allowing us to address novel biological questions of human thymus biology. In addition, we are determined to combine in vitro derived thymic epithelium with human T-cell progenitors either in vitro or in vivo. This is the logical next step in creating a very powerful novel tool to study diverse aspects of autoimmunity in a strictly human context.
If you have comments, questions, or would like to support our research, please directly contact Dr. Russ via email.
We are always on the look-out for motivated individuals at every career level to join the team! Please directly contact Dr. Russ with a motivation letter explaining why you want to join the lab, your CV and contact information for references.

Please also visit the Gates Center for Regenerative Medicine page and the Research Track page of the University of Colorado (selected Cell Biology, Molecular Biology, and Genetics)

Lab Members:
Principal Investigator: Holger A. Russ, Ph.D.
Ali Shilleh, Msc.
Shane Williams
, Bsc.

Publications

Education:
PhD: Tel Aviv University; Doktorvater: Shimon Efrat, 2011
Postdoctoral training: UCSF; Advisor: Matthias Hebrok, 2016

Please direct inquiries to specific e-mail addresses listed within individual entries. For all other general Research inquiries, please contact: Kathryn Gray, BFA, MA