R01DK127821

The Gut Endoderm: Origin, Formation and Fate - Project Summary / Abstract

The gut endoderm is the precursor tissue of the respiratory and digestive tracts, as well as their associated visceral organs. In this project, we will utilize a suite of state-of-the-art technologies to address fundamental questions regarding the mechanisms of mammalian gut endoderm cell lineage commitment and tissue morphogenesis. Additionally, we aim to probe the developmental origin and fate of cells that comprise the gut endoderm, using the mouse model.

Our previous studies have provided a paradigm shift in our understanding of the origin and mechanism of formation of the gut endoderm. Through fate mapping, live imaging, and more recently single-cell transcriptomic methods, we have demonstrated that the gut endoderm of mice consists of cells from two distinct developmental origins: embryonic definitive endoderm and extra-embryonic visceral endoderm. This dual origin challenges the prevailing view of germ layer formation in mammals, which posits that endoderm, along with mesoderm and ectoderm, derives solely from pluripotent epiblast. Furthermore, we have shown that the gut endoderm forms through a novel intercalation mechanism and identified SOX17 as a critical regulator of this process.

The broad aim of this project is to use molecular, genomic, embryological, and imaging techniques to investigate fundamental open questions pertaining to the origin, formation, and fate of the gut endoderm in mammals. Specific Aim 1 will investigate the dynamic cellular behaviors driving gut endoderm morphogenesis. Specific Aim 2 will probe the mechanism(s) by which the SOX17 transcription factor drives gut endoderm cell fate specification, tissue morphogenesis, and communication between embryonic definitive endoderm and extra-embryonic visceral endoderm cells as they form a congruent epithelium. Specific Aim 3 will determine whether descendants of extra-embryonic visceral endoderm cells persist throughout embryonic development and whether they will ultimately contribute to the endodermal organs of the adult.

A rigorous understanding of the normal gut endoderm, encompassing its origin, formation, and fate, will underpin logical efforts to direct the differentiation of cells into endoderm identities. This knowledge will also aid in generating bona fide endodermal organoids for development and disease modeling and screening. Additionally, it will help us understand disease progression and design new therapeutic strategies for these vital organ systems when they fail.

Sloan-Kettering Institute For Cancer Research

<P>THE GOALS ARE:</P><UL><LI>TO FOSTER FUNDAMENTAL CREATIVE DISCOVERIES, INNOVATIVE RESEARCH STRATEGIES, AND THEIR APPLICATIONS AS A BASIS FOR ULTIMATELY PROTECTING AND IMPROVING HEALTH;</LI><LI>TO DEVELOP, MAINTAIN, AND RENEW SCIENTIFIC HUMAN AND PHYSICAL RESOURCES THAT WILL ENSURE THE NATION'S CAPABILITY TO PREVENT DISEASE;</LI><LI>TO EXPAND THE KNOWLEDGE BASE IN MEDICAL AND ASSOCIATED SCIENCES IN ORDER TO ENHANCE THE NATION'S ECONOMIC WELL-BEING AND ENSURE A CONTINUED HIGH RETURN ON THE PUBLIC INVESTMENT IN RESEARCH; AND</LI><LI>TO EXEMPLIFY AND PROMOTE THE HIGHEST LEVEL OF SCIENTIFIC INTEGRITY, PUBLIC ACCOUNTABILITY, AND SOCIAL RESPONSIBILITY IN THE CONDUCT OF SCIENCE.</LI></UL><P>IN REALIZING THESE GOALS, THE NIH PROVIDES LEADERSHIP AND DIRECTION TO PROGRAMS DESIGNED TO IMPROVE THE HEALTH OF THE NATION BY CONDUCTING AND SUPPORTING RESEARCH:</P><UL><LI>IN THE CAUSES, DIAGNOSIS, PREVENTION, AND CURE OF HUMAN DISEASES;</LI><LI>IN THE PROCESSES OF HUMAN GROWTH AND DEVELOPMENT;</LI><LI>IN THE BIOLOGICAL EFFECTS OF ENVIRONMENTAL CONTAMINANTS;</LI><LI>IN THE UNDERSTANDING OF MENTAL, ADDICTIVE AND PHYSICAL DISORDERS; AND</LI><LI>IN DIRECTING PROGRAMS FOR THE COLLECTION, DISSEMINATION, AND EXCHANGE OF INFORMATION IN MEDICINE AND HEALTH, INCLUDING THE DEVELOPMENT AND SUPPORT OF MEDICAL LIBRARIES AND THE TRAINING OF MEDICAL LIBRARIANS AND OTHER HEALTH INFORMATION SPECIALISTS.</LI></UL>

93.847 - Diabetes, Digestive, and Kidney Diseases Extramural Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [HHS - NIH]

New York, New York 100656007 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-25-301)

Amendment Since initial award the End Date has been extended from 01/31/25 to 04/30/30 and the total obligations have increased 427% from $648,756 to $3,418,174.