Equine Laminitis: Cellular and Molecular Mechanisms Underlying Disease
Laminitis is a painful disease in horses and the 2nd leading cause of euthanasia. Laminitis results when the lamellae, which normally connect the hoof wall and the skeleton, are compromised and lose function. The lamellae are derived from skin and are folded to increase the surface area attaching epidermal tissues on the hoof side and dermal tissues on the skeletal side. These tissues are diagramed below.
Figure (left): Simplified diagram of horse foot (side view). HW is hoof wall, DP is distal phalanx. Lamellar tissue is outlined in purple. Area in blue box shown below in cross section.
Figure (right): Diagrams and images show cross-sections through lamellar tissue (parallel to the ground).
Top row: Interdigitating dermal (shaded pink in sketches) and epidermal (shaded blue in sketches) tissues link the skeleton (right side of sketches) to the inner hoof wall (left side of sketches). Middle row shows the two main epidermal layers (basal cells in pink, suprabasal cells in blue). Bottom row shows dysplasia in laminitic epidermis, marked by the green stained cells expanding beyond the single basal cell layer.
What do we want to investigate over the next year or two?
Project 1 addresses why basophils, a normally rare white blood cell, infiltrate lamellar tissue in huge numbers (our unpublished observations). Recently basophils have been implicated in human skin diseases, making them a good candidate contributing to laminitic tissue damage. The high basophil number indicates that a specific signal is calling these cells into the lamellae. We want to know what these signal(s) are and which lamellae cells produce them. We expect that stressed epidermal cells raise the alarm and call in basophils; inflammation and damage caused by basophils then begins a domino effect, causing more cell loss, and disease. We have candidate molecules for the signal and tools to identify them. If pro-inflammatory mediators, the "come hither" signals, are similar to those in human disease, therapeutic options would be available. The latter is a long-term goal and would not result from our initial studies.
Project 2 continues research on a cellular stress pathway that we found is active in endocrinopathy-triggered laminitis (including equine metabolic syndrome and PPID/Cushings disease). This endoplasmic reticulum (ER) stress pathway is active in many human diseases including type 2 diabetes and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Drugs to block steps in the ER stress pathway are under development. Over the last 2 years we discovered tools suitable for use in equine tissues and found activation of the ER stress pathway in chronic laminitis (some of our data is shown in the figures, a manuscript describing our results is currently in peer review for publication). Next, we need to look at earlier, acute states. We need to know whether ER stress is causing an active cell death process (apoptosis), and/or whether this stress pathway is driving incorrect differentiation of epidermal cells and loss of normal functions. Project 2 will dovetail with research in Dr. Galantino-Homer's lab examining ER stress in supporting limb laminitis. It's critical to know which arm(s) of the ER stress pathway are active in laminitis to know which drug classes will be most useful in the future.
Where will we get samples for study? Samples are available from archived tissues provided by Dr. Galantino-Homer and the Laminitis Discovery Database, Univ. Penn. School of Veterinary Medicine. Tissues were collected from horses undergoing euthanasia and donated for research.All research is conducted in accordance with local, state and federal guidelines.
Lynne Cassimeris, Ph.D.
Department of Biological Sciences
Hannah Galantino-Homer, VMD, Ph.D.
Senior Research Investigator
New Bolton Center
University of Pennsylvania
Julie Engiles, VMD
Associate Professor of Pathology
Department of Pathobiology-New Bolton Center
University of Pennsylvania
For the past 2 years, we have collaborated with Dr. Galantino-Homer at the University of Pennsylvania School of Veterinary Medicine and applied our nearly 35 years of research experience in cell and molecular biology to understand the cellular processes underlying tissue failure in laminitis. Our initial results drive the next research goals. We are asking for funding to allow us to pursue 2 projects, described in "Research Projects" section. We expect that each project will reveal steps in the disease process, and that together the two projects will provide a better understanding of why the lamellar tissue is compromised in disease.
Who will do the actual work and why do we need money?
Dr. Cassimeris will donate her time and will not receive any salary compensation. Drs. Galantino-Homer and Engiles are supported by the University of Pennsylvania and also will not require salary support for this work.
Funds are needed to design, develop and validate biological reagents for the research projects. We have available shared infrastructure and equipment needed for the proposed work and will not need to purchase any equipment, but we need funds to cover user fees associated with maintenance of high end equipment. Ideally, to speed research progress, financial support will allow us to hire a post-doctoral fellow or lab technician to perform the day-to-day experiments. A small Faculty Incentive Grant from Lehigh University allowed Dr. Cassimeris to hire an outstanding post-doc; even at part time effort, Dr. Da Silva Santos acquired data contributing to 3 manuscripts that are currently in preparation. Undergraduates will also participate in the research projects. Caitlyn Wilson (now in her first year at UC Davis School of Veterinary Medicine) is a co-author on a manuscript in preparation and has already co-authored two abstracts, one presented at a national conference and another at a local diabetes meeting.
Long term, we hope to be competitive for external support either from foundations or through federal grants from the National Institutes of Health (NIH) or the National Science Foundation (NSF). Dr. Cassimeris has been funded by NIH almost continuously during her 25 years directing an independent lab group at Lehigh. She has also received funding from NSF, as well as several other federal agencies.
Donate by check (payable to Lehigh University) and mailed to:
Lehigh University - Dept. of Biological Sciences
111 Research Dr.
Bethlehem, PA 18015
- or -
Click here to donate via Lehigh's Development Office.
Then enter information as outlined below.
Please specify that donation is for the LAMINITIS PROJECT.
Please be sure to specify under “other” that you are donating to the Laminitis Project.