Thematic Research Areas: Stem Cells
Information on this page is excerpted from
the University of Connecticut
Stem Cell website.
Stem Cell Research
In 2006, responding to the federal restrictions on the
creation of new stem cell lines for research, the Connecticut
General Assembly passed legislation that was signed into law by
Gov. M. Jodi Rell, authorizing the use of public funds to
finance human stem cell research. The law commits $100 million
over a period from 2007 to 2017 to support this highly promising
area of bioscience research.
While five states have passed similar legislation,
Connecticut, has set a new standard by becoming the first state
to actually implement a structured, ongoing research grant
program of this type. The law established a competitive process
for awarding research grants. An impartial Stem Cell Research
Advisory Committee, chaired by the Connecticut Commissioner of
Public Health, was appointed to distribute the funds based on
the scientific, legal and ethical integrity of the research
being done.
The first allocation of funds – totaling nearly $20 million –
was disbursed on November 21, 2006. Fifteen of the 21 research
proposals funded were awarded to UConn faculty. Collectively,
they amounted to nearly $12 million, or about 60 percent of the
total disbursal for 2007. The funding supports investigators
engaged in a wide range of research projects designed to unlock
the secrets of stem cells and turn them into effective
treatments for a host of diseases and disorders as quickly as
possible.
Below is a listing of UConn Health Center faculty who
received State of Connecticut Stem Cell Awards along with a
brief description of their research projects.
Hector
Leonardo Aguila
FACS isolation of progenitors and
generation novel cell surfaces antibodies.
In order for researchers to use stem cells for regenerative
therapies, the design of methods for the correct identification
of stem cells is crucial. One of the best approaches – not only
to characterize different cell types, but also to isolate them -
is the generation of antibodies against cell surface molecules.
The Project 2 group has developed unique tracking systems for
musculoskeletal development to visualize progenitor cells with
the ability to develop into cartilage, bone, fat and muscle.
These systems employ genetic techniques that add genetic
information to embryonic stem cells to make them express
fluorescent protein at defined stages of their development.
Gordon
G. Carmichael and
Asis Das
DsRNA and epigenetic regulation in
embryonic stem cells.
Embryonic stem cells are endowed with two remarkable
features. They have the capacity for self-renewal and to grow
indefinitely, and they also have pluripotency, the potential to
change into virtually any cell in the human body. The goals of
the project are to explore the key molecular factors that govern
“stemness,” and to develop technologies that will allow
manipulation of stem cells and their genes.
Stephen Clark
Correction of dermal lesions with hES derived progenitor
cells.
The goal of the project is to develop and test mice models
utilizing human embryonic stem cells in the treatment of skin
wounds. The work done in Project 9 is based on the hypothesis
that embryonic stem cells can participate in and/or improve the
skin wound healing process leading to a better resolution.
A. Jon
Goldberg and
Liisa T. Kuhn
Scaffolds to hold and mold progenitor
cells at a site of tissue regeneration.
Most of the projects in the grant focus on particular kinds
of tissues and learning how stem cells progress toward their
final tissue types, including identification of the essential
“signaling molecules” that direct the cells’ development, as
well as other necessary environmental factors. As those
questions are answered, the knowledge will be transferred to the
biomaterials scaffolds project, where methods for practical
clinical application will be developed.
Traditional reparative procedures for lost or damaged limbs
use prosthetics, such as the implants used in a hip or knee
replacement, made of metal, ceramic and plastic biomaterials.
These prostheses are meant to replace the damaged tissue or
organ, not to repair it. Cell-based therapies, on the other
hand, require reabsorbable biomaterials. They must carry in the
cells and define and shape the area of regeneration, but they
must also degrade or reabsorb so that newly grown tissues can
replace them. These types of biomaterials are called scaffolds
and they are porous, like sponges, so that the cells can be
contained inside the pores. Their purpose is to mimic the
natural environment inside the body in which cells are
accustomed to living. When biomaterials are made this way, they
provide a means of triggering the cell to start regenerating the
lost or damaged tissue. For the stem cell project, the
biomaterials group will synthesize novel scaffolds designed
specifically for musculoskeletal system regeneration.
Brenton
R. Graveley
Alternative splicing in human embryonic
stem cells.
In order to fully understand how human embryonic stem cells
work and to develop the ability to differentiate them into
specific cell types, it is essential to determine which genes
and proteins are expressed in stem cells. While many studies
have been conducted to clarify which genes are expressed in stem
cells, all of them have overlooked an important aspect of gene
expression - alternative splicing, the process by which a single
gene can give rise to multiple proteins by cutting and pasting
the RNA produced by the gene in different ways. The study will
aim to full this research gap.
Robert A.
Kosher and
Caroline Dealy
Generation of cartilage from hES derived
progenitor cells.
Degenerative diseases of cartilage are among the most
prevalent and debilitating chronic health problems in the United
States, and one of the main causes of decreased quality of life
in adults. While more than 90 percent of the population over age
40 have some form of cartilage degeneration, treatment is
particularly challenging because of the limited capacity of
cartilage for self-repair and renewal. Human embryonic stem
cells are a potentially powerful tool for repair of cartilage
defects and one of the major goals of the Project 7 team is to
develop culture systems and conditions that will allow stem
cells to uniformly differentiate into chrondrocytes, cells that
form cartilage.
Marc
Lalande
The role of epigenetics in disease and
development.
The Lalande lab is currently studying Angelman syndrome (AS),
one of the better-known causes of mental retardation. AS is a
neurogenetic disorder passed exclusively through the maternal
germline because of the epigenetic process called genetic
imprinting. Individuals with AS fail to inherit a normal active
maternal copy of the gene encoding ubiquitin protein ligase E3A
(UBE3A). Only the maternal copy of UBE3A is active in brain with
the paternal copy being silenced due to imprinting.
The loss of UBE3A in the brain of AS patients causes the
accumulation of proteins in the brain that result in the
clinical problems in AS. The accumulating proteins have not yet
been discovered, and the Lalande lab is attempting to identify
the targets of UBE3A. For these studies, the Lalande lab has
developed techniques to knockout UBE3A in stem cells and then
produce neurons from the UBE3A-negative stem cells. The
researchers are also investigating the molecular process that
silences the paternal UBE3A allele in the brain using a mouse
model of the disease. This work is supported by the Physicians
Health Services endowment.
James Li
Development of efficient methods for
reproducible and inducible transgene expression in human
embryonic stem cells.
Human embryonic stem cells (hESCs) are an unlimited source of
precursor cells that can be directed to differentiate into any
types of cells, which can then be used for regenerative medicine
and studies of toxicology and pharmacology, the studies of
poisons and drugs. How quickly and how efficiently researchers
will be able to use hESCs depends upon their capacity to
conveniently modify the development of hESCs into various cell
types as desired. Current techniques are inefficient and may
produce unpredictable results that limit their utility. The
purpose of this project is to use an enzyme called DNA
recombinase to recognize specific DNA sequences in a specific
position in the human genome and then efficiently replicate them
to compel stem cells to develop according to specific
requirements.
Zihai
(Zack) Li and Bei Liu
Embryonic stem cell as a universal
cancer vaccine.
Long before embryonic stem cells were used for genetic and
developmental studies, researchers understood that the ways in
which they can alter their form and replicate are similar to the
ways in which cancer cells grow and proliferate. This study is
grounded in the fact that immune systems can recognize antigens,
such as proteins, on the surface of tumor cells that have the
capacity to stimulate the production of antibodies. Most of the
current research on cancer vaccines target these antigens. The
researchers aim to explore the potential for using stem cells to
provide a universal cell-based vaccine against cancer.
Alexander
Lichtler
Directing ES cells to a common
progenitor cell for musculoskeletal tissue generation.
The researchers are striving to develop a method that will
use well-defined culture conditions to promote differentiation
of human embryonic stem cells into a pure population of mesoderm
cells, cells from the embryonic layer that ultimately develops
into all connective tissue, muscle, bone and the urogenital and
circulatory systems. Those cells would then be used by other
members of the grant team to differentiate into the type of
cells they are studying. Additionally, the Project 1 group will
be aiding Dr. Mina (Project 6), producing embryonic stem cells
equipped with fluorescent protein markers that come on when the
cells have reached a certain differentiation stage.
Mina Mina
Generation of bone via the neural crest
development pathway.
The cells that contribute to the facial skeleton, including
the bones and teeth, are formed from cells of the cranial neural
crest, the part of the embryonic ectoderm that develops into the
skull, spine and associated nerves. There is a significant body
of scientific evidence suggesting that differences in embryonic
origin and mode of ossification, the natural formation of bones,
in the bones of the face, skull and spine have significant
influences on various properties of the skeletal tissues at
those different sites. Consequently, effective cell-based
therapies for skeletal tissues in the skull and face depend upon
the capacity to identify and isolate stem cells capable of
appropriately regenerating skeletal tissues. Project 6 aims to
develop ways to generate and identify those cells.
David Rowe
Optimizing mesoderm derived bone cell
differentiation from hES cells.
The project will give researchers who have experience working
with mice stem cells directed to bone cell differentiation the
opportunity to apply their knowledge to human embryonic stem
cells. The research aims to provide objective criteria for
evaluating the potential of cells to develop in bone tissue
types with the goal of maximizing the potential to efficiently
differentiate cells to produce bone tissue.
Ren-He Xu
ChIP-chip analysis to screen target
genes of BMP and TGF signaling in human ES cells.
The project extends earlier research through which two
essential signaling pathways have been identified that governs
the early fates of human embryonic stem cells. One of these
pathways promotes the cells to differentiate, while the other
sustains their self-renewal. The research will seek to identify
genes that regulate both pathways.
Additional faculty conducting research in the area of stem
cells include:
Stephen J.
Crocker, Assistant Professor of Neuroscience, Ph.D.,
University of Ottowa. Stem cells; glia; metalloproteinases;
cytokines; development; pathology; tissue culture.
Xuejun
(June) Li, Assistant Professor of Neuroscience, Ph.D., Fudan
University. Stem cells; neural development and degeneration.
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