Pivotal and Diverse Roles for Matricellular Proteins in Musculoskeletal Disorders
Abstract
OVERALL PROGRAM Topic Area and Strategic Goals: This proposal addresses the Fiscal Year 2022 (FY22) Peer Reviewed Medical Research Program (PRMRP) Topic Areas: Orthopaedic Medicine: Musculoskeletal Disorders (related to acute and chronic bone conditions and injuries) and Arthritis. It also addresses the following four FY22 PRMRP Strategic Goals: (1) understand mechanisms underlying the pathobiology of associated musculoskeletal disorders; (2) develop strategies for improved care at point of injury to prevent musculoskeletal disorder onset; (3) develop and test novel and improved intra-articular treatments for joint injuries; and (4) develop and test strategies to increase quality of life or halt/slow disease progression, including regenerative medicine approaches and biologics for musculoskeletal disorders. Background: Injuries to the arms and legs – the extremities – are very common for our military personnel and civilians. Indeed, these extremity injuries are the most common battlefield injuries and also occur in non-deployed military personnel during training. Most extremity injuries affect the musculoskeletal system. These injuries are painful, result in loss of function and use, and result in expensive medical costs. Our project will investigate four different types of musculoskeletal disorders: (1) bone injury (fracture), (2) amputation (the loss of digits or limbs), (3) joint injury eventually causing degenerative joint disease also known as arthritis, and (4) the abnormal formation of bone in soft tissue following trauma (a disease condition called heterotopic ossification). These conditions affect military and civilian in the short-term (acute) immediately following injuries and over a much longer time course, spanning decades or a lifetime (chronic). Summary of Proposed Studies: Our goal is to study the role that certain molecules – proteins – play in the progression of these various disorders. The molecules we will study are called thrombospondins. There are two molecules – thrombospondin 1 and thrombospondin 2 – that are siblings. They are very similar in their structure, but interestingly, the proteins are produced by different types of cells and are present during different periods of healing. In the first aim of this study, we plan to dissect how these two molecules function differently in these various injury conditions by studying mice that have been genetically engineered to lack either one or both of these proteins in certain cell types only at certain times post-injury (conditional modification). We will use the most advanced innovative nucleic acid sequencing techniques to explore the specific cells that express the proteins and the impact that the absence of either thrombospondin 1 or 2 genetically has on the injury responses. Additionally, we will examine a suite of new drug therapies that target the function of the thrombospondins by either preventing their production or by activating or blocking their interactions with other proteins. The Program includes scientists from the University of Michigan, the University of Texas Southwestern (UTSW), and Vanderbilt University. In addition to the four projects focused on the aforementioned disorders, we also will develop two research hubs (one at Vanderbilt and one at UTSW) to enable the success of our research. Impact: Our study will provide an in-depth new understanding of traumatic injury responses. By studying thrombospondins, we will gain new insights into how to enhance bone healing, promote the regrowth (regeneration) of amputated digits and limbs, prevent the development of arthritis, and prevent the formation of bone that forms in soft tissue. Ultimately, we will characterize a novel set of therapies. These will be validated in mouse models, and at the end of the study we will be ready to take therapeutics to next steps in the process of drug and pharmaceutical development. PROJECT 1 Topic Area and Strategic Goals: The Fisc
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310327
Entities
People
- Kurt D. Hankenson
Organizations
- United States Army
- University of Michigan