# In situ analysis of functional endocrine, vascular, and immune cell interactions during early postnatal development of the human pancreas

> **NIH NIH U01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $632,286

## Abstract

If the causes of type 1 diabetes are not known it is mainly because the human pancreatic islet and its
interactions with the immune system have not been studied. The diabetes research community is now coming
to terms with the lack of relevance to the human situation of results obtained in rodent models of diabetes. In
response, there is a new concerted effort at obtaining and studying the relevant material, namely the human
pancreas, in health and disease. The long-term goal of this research program is to understand the anatomical
and physiological changes that occur in the human islet during the progression towards the diabetic state. The
objective of this application is to determine how the endocrine, vascular and immune compartments mature
and interact functionally during the postnatal development of the islet. We will focus on the juvenile maturation
period because it is a stage during which early-arising autoimmunity is strongly correlated with the
predisposition towards overt type 1 diabetes. The overarching hypothesis is that the onset of beta cell-directed
autoimmunity is causally related to developmental alterations in the molecular phenotypes of islet cells and to
changes in islet architecture. We propose that maturation processes make islets susceptible to inflammation
and facilitate the development of autoimmunity. The rationale for the proposed research is that understanding
what makes the islet vulnerable will not only help explain its downfall but also provide clues for intervention
strategies. This project is thus relevant to the mission of the NIH and is responsive to the research objectives
of the Funding Opportunity Announcement from the NIDDK entitled “High-Resolution Exploration of the Human
Islet Tissue Environment”. Guided by preliminary data, we will test our hypothesis by pursuing three specific
aims: (1) determine the mechanisms of functional maturation of islet endocrine cells, (2) determine how
endocrine control of vascular function is established, and (3) determine changes in the phenotype and
behavior of islet resident macrophages. Under the first aim, we will study the massive structural and functional
changes needed for beta and alpha cells to reach their full secretory potential. In all three aims, we will record
cellular responses with functional imaging and measure hormone release in living pancreas slices from donors
aged 0 to 10 years old. These studies will be complemented by scRNA-seq analyses of cells sorted from
isolated islets. Under the second aim, we will determine how the endocrine cells establish control of the
vascular pericyte, the major regulator of blood flow in the islet. Under the third aim, we will examine how the
phenotype and function of the islet resident macrophages changes during the maturation of the islet. The
proposed research is significant because the anticipated results could reveal developmental processes that
diminish the islet’s natural defenses and trigger abnormal responses from...

## Key facts

- **NIH application ID:** 10251144
- **Project number:** 5U01DK120456-04
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Marcela Brissova
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $632,286
- **Award type:** 5
- **Project period:** 2018-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10251144

## Citation

> US National Institutes of Health, RePORTER application 10251144, In situ analysis of functional endocrine, vascular, and immune cell interactions during early postnatal development of the human pancreas (5U01DK120456-04). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10251144. Licensed CC0.

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