Type 2 diabetes (T2D) is associated with significant complications that affect the normal function of the urinary and gastrointestinal tracts. The impact of aberrant bladder and/or gut motility ranges from discomfort in the case of urinary incontinence and diarrhea to life-threatening situations such as intestinal pseudo-obstruction. In spite of this significant healthcare burden, the mechanisms that underlie the development of bladder and GI dysmotility in diabetes, and the extent to which they can be reversed pharmacologically, are incompletely understood. As a result, the development of treatments to address smooth muscle dysmotility in diabetes has been hampered. Coordinated smooth muscle activity is central to the normal function of the bladder and gastrointestinal tracts, underlying both their storage and voiding/expulsion capabilities. Data from our group have identified a new function for neuropilin 2 (Nrp2) in regulation of smooth muscle. Deletion of Nrp2 in led to an increase in evoked contraction of bladder strips or colonic rings, but slower gastrointestinal transit. In mice with diminished bladder contractility secondary to partial bladder outlet obstruction, inducible SM-specific deletion of Nrp2 was found to restore SM contractility relative to Nrp2-intact mice. In this proposal, we hypothesize that Nrp2-regulated signaling is a novel, accessible target to control dysregulated smooth muscle activity in diabetes. We will test the hypothesis with the following Specific Aims: (1) Determine the impact of Nrp2 targeting on bladder and gut contractility in diabetes. (2) Interrogate neuropilin 2-regulated signaling networks in diabetes. We will employ functional analyses of bladder and gastrointestinal contractility and motility in mice with type II diabetes. We will delete Nrp2 in vivo using a CreLox approach to understand how bladder and gut contractility are influenced by Nrp2 deletion, in the context of diabetes. We will also employ a multiomics approach to interrogate the molecular basis of the physiological alterations observed in bladder and gut in diabetes. At the end of the project period, we will understand the extent to which manipulation of Nrp2 signaling restores the contractile capability of smooth muscle in the urinary and gastrointestinal tracts in diabetes, and the associated signaling networks that lie downstream of Nrp2. Successful completion of the studies would highlight the potential for therapeutic targeting of Nrp2 and its effectors in the context of diabetes.