Investigating the role of endothelial cells in intestinal regeneration and disease

PROJECT SUMMARY Significance: Intestinal dysfunction leads to diseases of enormous morbidity. Maintenance of intestinal stem cell self-renewal and differentiation is dependent on extrinsic signals from the supporting niche. Despite their abundance in the intestinal stem cell niche, the role of endothelial cells in supporting intestinal regeneration and facilitating repair after injury, remain largely understudied. Recently, Dr. Brisa Palikuqi reported that lymphatic endothelial cells, through the expression of the WNT modulator Rspo3, are essential for intestinal repair after cytotoxic injury. Yet, the role of blood vessel endothelial cells in intestinal regeneration and their dysfunction in inflammatory bowel disease, remains undetermined. By utilizing mouse models, immune profiling, single cell RNA sequencing and spatial transcriptomics, this Mentored Career Development Award proposal seeks to gain a comprehensive understanding of the role of blood endothelial cells in intestinal repair after injury and investigate changes in the blood endothelial cell niche in models of inflammatory bowel disease. Candidate and environment: The candidate for this Mentored Career Development Award, Dr. Brisa Palikuqi, is committed to leading an independent research group at the intersection of the fields of intestinal biology, endothelial cell biology and regenerative medicine. Dr. Palikuqi was trained in the laboratory of Dr. Shahin Rafii, at Weill Cornell Medicine, where she developed a three-dimensional platform for the vascularization of organoids and islet explants. During her postdoctoral studies at UCSF, in the laboratory of stem cell and developmental biologist Dr. Ophir Klein, Dr. Palikuqi has studied the role of lymphatic endothelial cells in intestinal regeneration. As described in her proposal, during the rest of the postdoctoral training and as she transitions to an independent position, Dr. Brisa Palikuqi plans to examine the role of blood endothelial cells in intestinal regeneration and inflammatory bowel disease. At UCSF, Dr. Palikuqi has assembled a team of mentors, advisors and collaborators that will support the successful completion of her proposed research and training. Career development: During the mentored period, the candidate will train in new techniques such as human and mouse intestinal models of regeneration and disease, single cell RNA sequencing analysis, spatial transcriptomics and immunology. The candidate will work closely with her mentoring team and enroll in complementary coursework to acquire the necessary expertise to accomplish the research and career goals proposed in her application. She will also undertake a program of training to support her professional development as a mentor and supervisor. A central goal of the mentored period is for the candidate to obtain a Principal Investigator position. The execution of the training in this proposal will equip the candidate with the necessary skillset and robust research platform to launch her independent research career.