Friday, April 26, 2024
4/26/2024
Retinal microvascular dysfunction is a common complication of diabetic retinopathy (DR), one of the leading causes of visual impairment in the working-age population. Although approved treatments and drugs can delay vision loss by several years, they do not benefit all DR patients, indicating that existing therapeutic tools do not affect all the mechanisms of microvascular dysfunction. Stiffening of the subendothelial extracellular matrix (ECM) is a prominent mechanical cue that increases endothelium rigidity, which is an age-related condition and a shared consequence of diabetes mellitus. Congruently, regeneration of blood vessels with optimal compliance properties is a major challenge in vascular regenerative therapies. We hypothesize that mechanical stabilization of the retinal microvasculature prevents/reverses retinal microvascular structural and functional damages and averts the sight threatening causes of DR. However, the molecular cues that regulate microvascular stiffness in the retina are major gaps in existing knowledge. In this project, we propose to test the hypothesis that the pericellular matrix protein referred to as cellular communication network 1 (CCN1) is a key regulator of retinal microvascular stiffness and that dysregulation of CCN1-derived signals in retinal ECs alters the mechanical properties of the microvasculature, ultimately causing functional deficits. CCN1 is a heparin- and integrin-binding protein acting primarily on endothelial cells (ECs) that produce it. CCN1-integrin signaling induces transcriptomic changes compatible with cytoskeletal remodeling mediated by actin binding proteins and Rho GTPases. Importantly, the CCN1 gene is induced in response to ECM stiffness through the yes-associated protein (YAP), a transcriptional co-activator that converts stiffness cues into gene transcription programs. In turn, the CCN1 protein attenuates YAP effects through a negative-feedback regulatory loop promoting relaxed cytoskeletal states repressive of YAP activity. Concordantly, levels of CCN1 were found to be substantially decreased whereas those of YAP were elevated in DR. We hypothesize that dysregulation of CCN1-YAP crosstalk is key to the alterations of microvascular compliance and function leading to DR. To test our hypothesis, we propose the following Aims. Specific Aim 1 determines the effects of CCN1 on the mechanical properties of retinal microvascular ECs cultured under normoglycemic and hyperglycemic conditions and defines the transcriptomic changes and signalomic cascades associated with CCN1 modulation of EC compliance. Specific Aim 2 is designed to determine the mechanical defects in the retinal vasculature upon CCN1 or YAP deletion in mice and tease out the mechanisms by which CCN1-YAP crosstalk maintains optimal retinal microvascular stiffness. Specific Aim 3 correlates CCN1/YAP alterations with stiffening of the retinal microvasculature in DR mouse models and the effects of targeting CCN1-dependent pathways on microvascular function in DR. These studies are expected to provide new mechanistic insights into the molecular effectors of retinal microvascular stiffness and determine the effects of CCN1-dependent stiffness pathways on retinal microvascular stability in DR.
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).
