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Friday, March 16, 2012

Laminitis Research Highlights Grayson Jockey Club Foundation's Research Lists for 2012


The Grayson-Jockey Club Research Foundation announced today that the charitable organization will fund 16 projects in 2012, totaling $845,646. The research includes the launch of eight new projects, continuation of eight projects entering their second year, and the Storm Cat Career Development Award.

Of special interest is the announcement that a project on laminitis has received the Elastikon™ Equine Research Award. This is funded in part through a contribution by Johnson & Johnson’s Consumer Products Company, manufacturer of Elastikon tape and other equine products.

Of particular interest are the following projects:

LAMINITIS STUDIES

1. Digital Hypothermia in Laminitis: Timing and Signaling
Dr. James Belknap, The Ohio State University (Second Year)

Dr. Belknap
The most recent figures from a study involving the USDA and State Veterinary Medical Officers project that at any given time laminitis affects 8 of every 1,000 horses in the United States. Based on the American Horse Council survey that there are 9.5 million horses in the nation, that would indicate 76,000 horses being affected at any given time. Of those affected, the USDA survey found that 4.7% died or were euthanized, or about 3,572 deaths from laminitis annually.

The authors of this project report that “an integrated research effort over the last decade has enhanced the current understanding of the pathophysiology of equine sepsis-related laminitis (one of numerous causes of the disease). This has mirrored progression of sepsis research in human medicine by moving from (an earlier) concept . . .to determining that a marked inflammatory injury takes place and is likely to play a prominent role in tissue injury and subsequent failure.” However, there have been persistent failure of systemic therapies for organ/laminar injury in both human and equine medicine. One advantage laminitis presents is that it effects the hoof rather than visceral organs, lending itself to artificial cooling more readily.

In a present project funded by the Foundation, digital hypothermia (cooling of the hoof) prior to onset of carbohydrate overload-induced equine sepsis resulted in dramatic decrease in laminar inflammatory signaling. The next goal is to find pharmaceutical therapies which can accomplish the same without the cumbersome aspects of maintaining constant hypothermia to the equine hoof (hooves).

2. Laminar Energy Failure in Supporting-Limb Laminitis
Dr. Andrew Van Eps, University of Queensland (Second Year)

Dr. Van Eps
A frequent and disheartening result of injury repair is that the leg opposite the one injured develops laminitis. This is known as supporting-limb laminitis and is what eventually caused Barbaro to be euthanized. Although it is a common occurrence, the mechanisms of the malady have not been established.

Dr. Pollitt
This project is headed by a young researcher, Dr Andrew Van Eps, but the co-investigators are world renowned Drs. Dean Richardson and Chris Pollitt.

The project involves testing the hypothesis that supporting-limb laminitis is a result of reduced blood supply to the connection between hoof and bone (lamellar tissue). Further, that the blood supply in normal circumstances is encouraged by a regular loading and unloading of the legs and hooves (alternating which one is bearing the most weight). Injury to one leg interrupts that alternating pattern.

Dr. Richardson
The researchers will test the hypothesis with a state of the art, minimally invasive technique known as tissue microdialysis in conjunction with three dimensional computed tomography to develop effective methods of preventing or minimizing lamellar tissue energy failure. Comments in the Research Advisory Committee evaluations included “may well provide immediately applicable strategies to prevent supporting-limb laminitis” and “really nice grant, new idea about a devastating problem.”

Support-limb laminitis is a special area of research interest for the researchers funded by the Grayson Jockey Club Foundation. It is believed to be a unique form of the disease that is precipitated by prolonged weightbearing on one hind limb or one front limb, caused by the opposite (injured) limb's inability to bear weight after surgery or injury. Tragically, the overburdened "good" or "supporting" limb develops laminitis in this scenario. (Hoofcare + Lameness photo)

3. Laminar Signaling in Supporting-Limb Laminitis
Dr. James Belknap, The Ohio State University– First Year (2 Year Grant)

A recent USDA study indicates that approximately 1% of all horses in the USA suffer from laminitis at any given time, and approximately 5% of those animals die or are euthanized while many others remain crippled. Of the conditions which create laminitis, the development of the disease in the supporting limb of an already injured horse is one of the worst, since it is believed that 50% of those cases result in euthanasia.

The author reports that while there are hundreds of published papers in the literature about other forms of laminitis, reports on supporting-limb laminitis are restricted to clinical reports and case studies.

This project will “introduce a novel, non-painful model of supporting-limb laminitis and will allow for cutting edge bench research techniques to not only (1) test the current hypotheses on the cause of laminar failure, but also (2) provide an unbiased technique to determine the cellular events that occur . . .”

The investigator has performed a number of laminitis project for Grayson and the USDA, and has a well developed set of tools and techniques including laser micro-dissection of frozen laminar cells and an advanced “functional genomic” technique called RNA-Seq. By applying these techniques that have previously characterized laminitis caused by sepsis or metabolic syndrome to support limb laminitis, we will get our first understanding of what kind of drugs and treaments might prevent it.

This grant was selected by the board to receive the sixth annual Elastikon™ Equine Research Award.

4. Stem Cell Homing after IV Regional Limb Perfusion
Dr. Alan Nixon, Cornell University (First Year of Two-Year Grant)

Dr. Nixon
“The initial fervor associated with stem cell therapies has been tempered by mediocre clinical results,” states Dr. Nixon, long recognized as a key leader in quest to maximize use of stem cells. “More can be done, including pre-differentiation, gene-directed lineage targeting, and more efficient delivery.” This proposal will deliver by “local vein injection, to back-flow to bowed tendon and other disease conditions such as founder and traumatic arthritis.”

Transplanted cells then exert normalizing and restorative effects . . .” The long-range goal is to provide a simplified approach to stem cell therapy. We cannot do this without verification of cell homing and impact. (The project) will map stem cell distribution in the tendons, ligaments, and joints of the forelimb after direct venous injection.”

LAMENESS STUDIES

1. AAV-IRAP Gene Therapy to Prevent Osteoarthritis
Dr. Laurie Goodrich, Colorado State University (Second Year)

Dr, Goodrich
Osteoarthritis is a common affliction in horses, and current methods of treatment are effective only in reducing the pain, at best. This proposal will utilize gene therapy, which is a technique in which cells can be genetically modified or “re-programmed” to produce beneficial protein that will allow cartilage to heal. The initials in the project title stand for Adenoassociated Virus and Interluken Receptor Antagonist Protein. If cells in the joint could be re-programmed to produce IRAP, the devastating effects of joint inflammation could be halted and the progress of osteoarthritis could be reversed.

These researchers’ preliminary work utilizing AAV-IRAP suggests that cells of joints are easily re-programmed to produce beneficial protein. The aims of this project is to define the most appropriate dose of AAV-IRAP that will result in effective levels and answer the question of whether this approach can prevent osteoarthritis in the horse.

2. Investigation of Cell and Growth-Factor Dependent Tenogenesis
Dr. Martin A. Vidal, University of California-Davis (Second Year)

Dr. Vidal
The crux of this study is to test preliminary indications that a newly developed in vitro tendon/ligament culture model will prove effective at determining the optimal cell type from bone marrow, fat tissue, umbilical cord, tendons, ligaments, and muscle to use in tendon and ligament repair. The model also will allow investigators to learn the early molecular and cellular signals in tendon and ligament tissue formation.

The author states that current methods of healing result in inferior scar tissue and re-injury rates ranging from 23% to 67%. Transforming growth factor (TGF) combined with platelet rich plasma will be utilized, and tests will be done on how they affect tissue growth, strength, and composition. ”

3. Stem Generation of Equine Induced Pluripotent Cells for Regenerative Therapy
Dr. Lisa Fortier, Cornell University (Second Year)

Dr. Fortier
Stem cell based therapies are among avenues being tested with the goal of tendon cell regeneration to address tendonitis. The types of stem cells used so far may improve the structure of tendon healing, but appear to have limited regenerative ability or are limited due to potential issues of immune rejection.

The author explains that, “ . . . this proposal is to generate induced pluripotent stem cells (iPS cells) from equine adult dermal fibroblasts. iPS cells are the only stem cells that are both pluripotenent and autogenous, making them the most useful for clinical application. The expectation is that the results of the studies in this proposal will provide the first published description of the generation and characterization of equine iPS cells.” This is part of a process of testing the overall hypothesis that equine iPS cells will enhance tendon regeneration in cases of tendonitis.

Also, “the technical expertise gained in this study could be used in the future to generate autogenous iPS cells for use in equine cartilage and neuronal regeneration studies.”

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