Therapeutic Potential of Increasing Lymphangiogenesis in a Mouse Model of ALS
Abstract
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig s disease, is the most common adult motor neuron degenerative disease. Motor neurons in the brain connect to motor neurons in the spinal cord and together control the contraction of skeletal muscles and hence all movements -- walking, talking, eating, breathing, etc. ALS causes progressive fatal demise of brain and spinal cord motor neurons, which gradually impairs muscle action leading to loss of nerve-muscle contact (a.k.a. denervation), paralysis, and eventually death. ALS symptoms vary among different people, but most cases start in late middle age with muscle weakness or fatigue in arms and/or legs, slurred speech, or muscle cramps that worsen slowly. Bit by bit, patients lose their ability to perform common movements until, on average 3-5 years after initial detection, death comes when the paralysis hits breathing muscles. Besides older age, known risk factors include male sex, genetic family history and, interestingly, military service with Veterans having twice the disease prevalence of civilians. Currently there is no cure for ALS and, despite more than 40 clinical trials, there are only two FDA-approved drugs for the specific use in ALS patients that provide very limited benefits. There is an urgent need for new therapies that significantly reduce patient functional decline, increase survival, and improve quality of life. For this, research on new ways to approach the problem is critical. Other than genetic mutations that underlie approximately 10% of cases, causes for the vast majority of ALS cases are unknown and diagnosis usually happens when symptoms are very advanced. The variability of ALS onset and progression is explained in part by the multitude of molecular and cellular processes, whose dysfunction can lead to motor neuron death. However, most ALS cases share alterations of the biological process known as inflammation, a natural transient reaction of the body to tissue damage or infection that becomes harmful when it lasts too long or affects normal tissue. Dysfunction of the immune system and its component cells is part of pathological inflammation. Aberrant inflammation in the spinal cord, (a.k.a. neuroinflammation), and other tissues like skeletal muscle accelerates the progression of ALS and can lead to motor neuron death. In this application, we propose to investigate a new way to normalize inflammation in ALS by manipulating the lymphatic system. In organs other than brain and spinal cord, such as skeletal muscle, the lymphatic system runs parallel to the blood vasculature and is responsible for recycling of interstitial fluid from tissue. In addition, the lymphatics regulate the immune response by serving as active conduits for the passage of white blood cells and immune cells. It is increasingly recognized that lymphatics are also present in the brain and spinal cord, where they seem to play similar functions as in other organs. Generation of lymphatic vessels is a dynamic process that can be induced by overproduction of the protein vascular endothelial growth factor-D (VEGF-D). VEGF-D acts through binding to another protein, the VEGF-D receptor (VEGFR-3). Experimentally enhancing lymphatic vessel generation with VEGF-D resolves abnormal inflammation and improves the disease course in animal models of systemic diseases such as hypertension, skin inflammation, rheumatoid arthritis, and inflammatory bowel disease. Moreover, our preliminary data show that loss of the nerve-muscle connection in normal mouse muscle leads to decreased lymphatic vessel density and that lymphatic function can be normalized by overexpression of VEGF-D selectively in skeletal muscle. In addition, our data also show that lymph transport may be defective in mice that model ALS. Thus, we hypothesize that experimentally increasing lymphatic vessel abundance in the muscles or spinal cord of the superoxide dismutase 1 - Glycine 93-to-Alanin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210678
Entities
People
- Mendell Rimer
Organizations
- Texas A&M Health Science Center
- United States Army