Route 28 Summits

1999 Route 28 Summit Participants and Proposal Competition

 

 

 

 

 


Therapeutic Potentials of Neural Stem Cells

99 Summit Topic / 99 Speakers and Schedule / 99 Location / 99 Participants and Proposals

 

1999 Summit Participants and Proposals

The 1999 Chalenges

Problem 1. Spinal cord injury - Groups 1, 2, 3 (Green Teams)

A middle-aged man becomes quadriplegic due to a spinal injury sustained in a car accident 12 months ago. The spinal cord lesion epicenter is a c4-5 resulting in a devastating loss and atrophy of axons, spinal neurons and glia. A clinical work up suggests that this patient's lesion is incomplete, exhibits conduction deficits at the lesion site and contains a central necrotic core

• Identify the relevant repair issues that are important to this injury
• Describe which issue you would address and why.
• Outline a research proposal based on your rationale.

Problem 2. Degenerative Disease - Groups 4, 5, 6 (Red Teams)

Huntington's, Parkinson's, and Alzheimer's disease are devastating degenerative disease that affect gaba-ergic (striatum), dopaminergic (substantia nigra) or cholinergic neurons, respectively.

• Describe which disorder and repair issue you would address and why.
• Identify the relevant repair issues important for this disease.
• Outline a research proposal based on your rationale.

Problem 3. Stroke / Ischemia - Groups 7, 8, 9 (Blue Teams)

Stroke and ischemic injury can occur throughout the brain resulting in long-term deficits. Consider irreversible insults to the temporal cortex, corpus callosum or cerebellum.

• Identify the relevant repair issues that are important to each of these brain regions.
• Describe which insult model you would address and why.
• Outline a research proposal based on your rationale.

Teams:

Spinal Cord Injury Teams (Green) Neurodegeneration Teams (Red) Stroke Teams (Blue)
Group 1

Carol Hicks

UCLA

Leonard L. Jones

UCSD

Jack M. Parent

UCSF

Lamya S. Shihabuddin

Salk Institute

Group 4

Christoph Redecker

Heinrich-Heine

Nansheng Chen

UBC

Candace Floyd

Med Col of Virg

Liza Bundesen

Georgetown

Uwe Konietzko

Salk Institute

Group 7

Jenny Cheng

UBC

Elad Gil

MIT

Andrew Hartmann

INSERM

Chichung Lie

Salk Institute

Jo Velardo

U Florida

Group 2

Andrew Willhoite

UCSD/Salk

Christopher Chambers

Northwestern

Helen Fillmore

Med Col of Virg

Manfred Biebl

U. Regensburg

Wendy Walwyn

UCLA

Group 5

Armin Blesch

UCSD

J. Leigh Humm

UT Austin

Caitlin Hill

Ohio State

Joerg Dietrich

U Regensburg

Raewyn Seaberg

U Toronto

Group 8

Christine Brazel

Penn State

Rick Cohen

NIH, NINDS

Stefan Haas

U Rostock

Viorica Pencea

Emory

Xinyu Zhao

Salk Institute

Group 3
Mathew Easterday UCLA
Karen Chandross NIH-NINDS
Hynek Wichterle Rockefeller
Kap Holloway Med Col of Virg
Sebastien Couillard-Despres U. Regensburg
Group 6

Uchida, Nobuko

Stem Cells Inc

Biran, Roy

U Utah

Christie, Brian

Salk Institute

Horky, Laura

UCSD

Frost, Emma

Unifmd Serv U Health Sci

Group 9

Tim Brazelton

Stanford

Patricia Burroughs

UCLA

Christiana M. Cooper

U Regensburg

Holger Jahn

U Hamburg

Hongjun Song

Salk Institute

Proposal Review Committee Members:
Bruce Ransom, Chair
Ross Bullock
Emanuel DiCicco-Bloom
Marie-Francoise Chesselet
Mark Nobel
Dennis Choi
Derek van der Kooy
Evan Snyder
Betsy Moore
Juergen Winkler
Tailoi Chan-Ling

Winning Proposal Abstracts:

Proposals were evaluated with equal weight given to the quality and inventiveness of a detailed written proposal as well as the creativity and clarity of an oral presentation.

Spinal Injury

Group 3: Mechanical force mediated extension of corticospinal axons across injured spinal cord

Mathew Easterday, Karen Chandross, Ph.D. , Hynek Wichterle, Kathryn Holloway, M.D. , Sebastien Couillard-Despres, Ph.D.

Injury to the spinal cord often results in the loss of cortical innervation to the spinal motor neurons with subsequent loss of motor control. Treatment of this deficit requires that the axons from surviving cortical neurons present proximal to the injury must cross the lesion site and reinnervate their original targets. Although, attempts have been made to promote regrowth of severed axons by introduction of permissive environments at the site of injury, these experiments provide limited recovery of motor function because regenerating axons are inefficient at traversing the longitudinal extent of the degenerated spinal cord. It has been shown that during development there are two phases of axonal growth. First, the axons grow for relatively short distances before they reach their target region. Upon reaching their target, growth of the entire organism provides a mechanical force that extends axons to up to 100 times longer than their original length. The axons’ capacity for mechanical elongation has been previously demonstrated by exerting force on axons in vitro (Lamoureux et al., 1992). Here we propose that this second phase of axonal elongation (i.e., driven by mechanical force) is being ignored in current strategies for spinal cord repair which typically attempt to recreate the molecular fetal environment while neglecting the vast difference in length between fetal and adult spinal cords. We propose to make use of the viscoelastic properties of axons by subjugating them to mechanical force using magnetic beads and exposing them to a directional magnetic field.

Our specific Aims include

1) optimizing the attachment of axonal growth cones to magnetic beads

2) establishing an in vitro paradigm to guide axons through longitudinal slices of adult spinal cord tissue

3) remyelinating newly formed axons using oligodendrocyte progenitors cells

An in vitro model will allow us to assess optimal conditions for axonal attachment to the beads, rate and extent of axonal elongation, the effects of spinal cord tissue on induced axonal movement, and the extent of remyelination of newly elongated axons. This approach also eliminates the dependence on the intrinsic ability of the axon to migrate through the hostile environment of the glial scar. It is expected that these studies will provide a new approach to help guide axons through the injured spinal cord and innervate their targets, independently of extracellular cues. Moreover, these studies may lead to invivo therapeutic approaches that promote long distance axonal growth and might be useful for both acute and chronic spinal cord injuries.

 

Neurodegeneration

Group 4: Cell Replacement and Gene Targeting Strategies During Different Life Stages in a Transgenic Model of Huntigton’s Disease

Christoph Redecker, M.D., Nansheng Chen, Ph.D. , Candace Floyd, Liza Bundesen, Uwe Konietzko, Ph.D.

Huntington’s Disease is an autosomal-dominant relentlessly progressive neurodegenerative disease with relatively late onset of clinical symptoms usually in the fourth decade of life characterized by a choreiform movement disorder with accompanying psychiatric and behavioral abnormalities. In contrast to Parkinson’s and Alzheimer’s, this disease is linked to the mutation of a single gene, enabling an early diagnosis and probably a specific cell replacement and/or gene targeting therapy. The mutation in patients with Huntington’s Disease is an expanded CAG/polyglutamine repeat of the huntingtin gene that induces a loss of GABA-ergic neurons in the striatum and cortex. The period before disease onset likely represents a time window for early therapeutic interventions targeted toward delaying disease onset, reducing the severity, and prolonging life. The plasticity of the young nervous system provides a uniquely favorable environment for the functional integration of transplanted stem cells.

The recent development of the YAC mouse model, a transgenic mouse that expresses 72 CAG/polyglutamine repeats and shows similar neurological abnormalities described in humans, allows us to test two different approaches:

1. To delay onset and probably reduce severity of Huntington’s disease by using an early cell replacement strategy to supplement dysfunctional neurons with transplanted stem cell derived neurons. Transplantation of neuronal progenitors into the early postnatal (i.e. plastic) striatum gives them a high probability to integrate into the host circuitry. Following transplantation, animals are evaluated for morphological/cellular characteristics and behavior.

2. Assuming that the huntingtin protein has essential functions in development but not in the adult, we intend to block expression of the protein in adult diseased striatal neurons. This will be achieved by viral targeting of an inducible expression system for antisense RNA against the Huntingtin/poly CAG message. The main advantage of this proposal is to test different types of interventions prior to onset of fully expressed Huntington’s disease.

Stroke/Ischemic Injury

Group 7: The Contribution of Adult Hippocampal Neurogenesis to Recovery from Stroke/Ischemia

Jenny Cheng, Elad Gil, Andreas Hartmann, M.D., Chichung Lie, M.D. Jo Velardo, Ph.D.

Stroke is the third leading cause of death in the United States today and costs American society over 100 million dollars in health care expenses each year. The debilitating functional deficits of stroke are the result of widespread damage to, or death of, neurons and glia as a consequence of ischemia. Some of this lost function may be recovered, depending on the location and severity of the ischemic event. It has been postulated that neurogenesis in the adult animal, rewiring of neuronal circuits, or a combination of the two processes is the causative mechanism of this recovery. Recent studies have demonstrated that new neurons are constantly generated in a variety of regions in the adult CNS. Despite concomitant functional recovery from ischemic damage and apparent neurogenesis, to our knowledge the contribution of adult neurogenesis to functional recovery has not been demonstrated.

Using a well-established model of hippocampal ischemia in conjunction with the Morris water maze task and a functional evaluation of adult neurogenesis, we will attempt to determine if newly generated neurons in the subgranular layer of the dentate gyrus neurons facilitate the recovery of working spatial memory following transient common carotid artery occlusion. In addition, we will determine if the level of endogenous functional improvement can be modulated by employing a strategy that enhances the survival and total number of new dentate neurons. Since ischemia is a major component of secondary injury processes in both neurotrauma and neurodegenerative disease, elucidation of endogenous repair mechanisms operating in response to ischemic events will lay the foundation for the development of effective therapeutics for a number of neurological conditions.

 

Aditional Proposal Abstracts

99 Summit Topic / 99 Speakers and Schedule / 99 Location / 99 Participants and Competition

 

 

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