Primary Appointment: Assistant Professor of Pediatrics
Secondary Appointment: Department of Immunology and Microbiology, University of Colorado
Director, Disease Modeling and Molecular Core, Barbara Davis Center for Diabetes
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
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
β Cell replacement: improving on the design
Castro-Gutierrez R, Michels AW, Russ HA.
Curr Opin Endocrinol Diabetes Obes. 2018 May 24. PMID: 29846237
Congratulations to Assistant Professor Holger Russ on being the recipient of the Peter Culshaw Family Junior Investigator Award in Diabetes. Dr. Russ’s research includes a multilayered approach to design beta cells from stem cells using state of the art genome editing technologies. If successfully incorporated, this could result in great benefit for diabetic patients and improve clinical results for cell replacement therapy.
Congratulations to Stephan Ramos for being awarded a T32 "Pre-Doctoral Training in Molecular Biology" grant for the second time (NIH-T32-GM008730).
Roberto Castro Gutierrez, BS
Graduate Student, Molecular Biology Graduate Program
Interested in developing a human stem cell therapy for Type 1 Diabetes using genome engineering technology and integrated immune system analysis.
Interested in the clinical applications of humanpluripotent stem cells, specifically their use in modelling development and disease.
Summer Student, CU Denver
Currently working on characterizing CX36 in hES derived beta cell clusters with Dr. Docherty.
Joseph Patrick O'Brien
Summer Student, Middlebury College
Currently working on optimizing the beta cell differentiation through single factor testing with Dr. Docherty. I'm also working on a project with Dr. Russ to recapitulate the pancreatic niche by establishing ALI co-cultures with vascular progenitor and endocrine cells.
Stephan Ramos, BS
Pre-Doctoral Student, Molecular Biology Graduate Program
Interested in investigating the molecular mechanisms of FOXN1 mediated thymic development and homeostasis in humans, and in elucidating the mechanisms of negative T-cell selection, and how issues in negative selection may give rise autoimmune disorders. Funding: T32 Molecular Biology training grant.
Graduate Student, Cell Biology, Stem Cells and Development Graduate Program
Interested in determining the underlying drivers of beta cell interconversion and heterogeneity in healthy and diseased states.
Taylor M. Triolo, MD
Fellow: Pediatric Endocrinology
Children’s Hospital Colorado and the Barbara Davis Center for Diabetes
Interested in generating functional beta cells from T1D patient derived iPS cells and the epidemiology of development of T1D in twins and siblings of patients with T1D.
Funding: NIDDK T32 Training Program Developing Pediatric Endocrinologists for the Future
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).
PhD: Tel Aviv University; Doktorvater: Shimon Efrat, 2011
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: Patricia Dodson