Grants

On December 9th 2023 from 4-9pm at Junction Plaza park in West Seattle we are having a free community holiday festival allowing everyone to submit their artificial intelligence generated art to be projected onto a 7 story building which will be shown for one week after the festival.

— – $30K

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AI Driven Drug Discovery Pipeline for Lead Optimization: from Virtual Screening to Preclinical Validation of Brain-Penetrant AD Therapeutics

open

NIA - National Institute on Aging

Summary In this proposed research, we aim to develop AI-driven virtual screening pipelines to screen billion-scale compound libraries and predict blood-brain barrier (BBB) permeability, which are critical steps for identifying drug-like lead compounds against AD/ADRD targets, as the current computational methods do not adequately address these crucial needs. First, we will incorporate small molecule foundation models, Bayesian ensemble learning, and active learning to accelerate the docking-based virtual screening pipeline, enabling efficient virtual screening of billion-scale compound libraries. Second, we will incorporate Affinity Selection Mass Spectrometry (ASMS)-based screening and advanced AI/Computational tools to enable similarity-based virtual screening (SBVS) for AD/ADRD targets when their ligand-bound structures are not known. Finally, we will construct a large- scale ΔGSolv dataset and take advantage of the dataset to develop AI/ML models that predict Kp,uu and Pgp ER, providing a more nuanced understanding of brain penetration for small-molecule brain penetrant drugs.

AI-guided Intestinal stem cell activation for mucosal restoration in ulcerative colitis

open

NIAID - National Institute of Allergy and Infectious Diseases

ABSTRACT The mucus layer of the digestive system plays a key role in innate immunity, protecting intestinal epithelium from commensal bacteria, pathogens, and toxins. Goblet cells (GCs), secretory cells residing in the intestinal epithelium, are essential for mucin secretion to form this protective mucus layer and maintain its integrity. Ulcerative colitis (UC) is strongly correlated with a compromised colonic mucus layer and a decrease in the number and function of GCs, eventually resulting in inﬂammatory ﬂare-ups. Unfortunately, current UC treatments display only limited eƯicacy and high recurrence rates, and mostly target the inﬂammatory process, without inducing mucosal regeneration. In this proposal, we aim to leverage the powerful regenerative potential of the patient’s own cells by activating colon-resident intestinal stem cells (ISCs) to diƯerentiate into GCs. We hypothesize this will augment mucus secretion and rebuild the broken mucosal barrier, eventually preventing pathogen invasion and the consequent inﬂammatory cascade. Accordingly, the ﬁrst aim of our study will include artiﬁcial intelligence (AI)-guided identiﬁcation of small molecules that boost GC diƯerentiation. We plan to build on our expertise in ISC diƯerentiation, combined with leveraging existing large biological datasets, including multi-omics datasets and chemical libraries to identify compounds that stimulate GC diƯerentiation. Our second aim is evaluation of AI-identiﬁed compounds in UC murine colon organoids (colonoids), and in colonoids derived from UC patients’ biopsies for identiﬁcation of the most potent GC inducers in this clinically relevant in-vitro model. Our third aim will be dedicated to assessing the therapeutic impact of the top GC boosting molecules in an acute UC murine model. Our proposed strategy to harness the innate stemness of colonic ISCs is envisioned to result in renewal of the colonic GC pool, enhancement of GC-induced mucus secretion and restoration of the mucus barrier function and its key role in innate immunity. We believe the potent stem-cell boosting molecules identiﬁed in this study may eventually be developed into a novel treatment modality to replenish the mucus layer and signiﬁcantly ameliorate inﬂammatory ﬂares and related symptoms in UC patients.