Saturday, December 21, 2024
12/21/2024
Diabetic foot ulcers (DFUs) are the leading cause of lower extremity amputations in the US and are responsible for more hospitalizations than any other complication of diabetes. The sheer number of diabetic ulcers that progress to amputation underscores the inadequacy of conventional therapies and the need for novel approaches. Phagocytic leukocytes - particularly neutrophils - play a major role defending wounds from invading pathogens. Yet, despite excessive neutrophil influx and persistent non-resolving inflammation, DFUs are highly vulnerable to infection with pathogenic bacteria, such as Pseudomonas aeruginosa and Staphylococcus aureus, which further contribute to their impaired healing. Although, impairments in the diabetic neutrophil’s bactericidal functions have been blamed for this major co-morbidity, what causes these impairments and whether they can be corrected or overcome, remain poorly understood. Recently, we demonstrated that neutrophil trafficking is delayed in diabetic wounds, and this delay in neutrophil response, renders diabetic wounds vulnerable to infection early after injury, which in turn exacerbates wound damage and impairs healing. We further showed that reduction in the formyl peptide chemokine receptors (FPR) in diabetic neutrophils (due to high glucose) is responsible for this delay. We found some auxiliary receptors (e.g., CCR1) that remained functional under diabetic conditions but they were not functioning because of their ligands were not adequately expressed in diabetic wounds during the acute phase of healing early after injury. Importantly, we showed that one-time topical treatment with CCL3 (a ligand for CCR1) restored the dynamics of neutrophil and inflammatory responses in diabetic wounds, which in turn reduced infection by >99%. CCL3 treatment also substantially improved wound healing in diabetic mice. Diabetic neutrophils are known to have impairments in their bactericidal functions, although it remains unclear what causes these impairments. It remains unclear how neutrophils (recruited into diabetic wounds by CCL3 treatment) could destroy bacteria and reduce infection if they have bactericidal functional impairments. In this proposal, we will determine the molecular mechanism(s) underlying impaired antimicrobial functions in diabetic neutrophils (Aim 1). We will also evaluate CCL3 therapeutic doses and assess their efficacies and safety profiles in diabetic mice and diabetic pig models (Aim 2). If we are successful, our studies will fill crucial scientific gaps and reveal mechanistic insights regarding defective mechanisms underlying impaired bactericidal functions in diabetic neutrophils. They will also determine the optimum dose(s) and delivery mechanism of CCL3 for topical clinical use to control infection and to stimulate healing in diabetic wounds. Aim 2 will also enable us to obtain an IND for topical therapeutic application of CCL3 in human diabetic patients with non-healing ulcers and has the potential to be applicable to all wounds.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).