User:HIRN Human Islet Research Network/sandbox

Human Islet Research Network

Founded	2014
Focus	To support collaborative research related to the loss of functional beta cell mass in type 1 diabetes (T1D).
Location	City of Hope in Duarte, California
Area served	International
Method	Collaborative Research
Key people	John Kaddis, Joyce Niland
Website	hirnetwork.org
Remarks	Supported by the National Institute of Diabetes and Digestive and Kidney Diseases and the Type 1 Diabetes special funding program.

The Human Islet Research Network (HIRN), is a collaborative research project whose mission is to better understand how human beta cells are lost in type 1 diabetes and to find innovative strategies to protect or replace functional beta cell mass in diabetic patients.

History

Human islets are small clusters of hormone-producing cells that make up a tiny fraction — less than 2 percent — of the pancreas. One type of cell in the islets, known as the "beta cell" produces insulin and releases it into a person's bloodstream when the amount of glucose (sugar) increases. In type 1 diabetes (T1D), those beta cells are destroyed by the immune system, hence the notion of why the disease is referred to as "autoimmune" (i.e., self-directed). Without beta cells, individuals with T1D lose the ability to make their own insulin and must have their insulin provided, either by injections or by a pump. While insulin therapy is lifesaving, it is not a perfect substitute for healthy beta cells, in that sometimes too much or too little insulin is injected. In 2014, the National Institutes of Health (NIH) launched the Human Islet Research Network (HIRN), a new team science effort to better understand why beta cells are lost in T1D and to find new ways to protect or replace beta cells in those with the disease.

HIRN brings together an international group of more than 90 scientists with complementary but diverse expertise and technologies, including cell biology, immunology, microfluidics, advanced imaging, bioengineering, genetics and animal model development. The scientists are organized into five consortia — the Consortium on Beta Cell Death and Survival (CBDS), the Consortium on Human Islet Biomimetics (CHIB), the Consortium on Modeling Autoimmune Interactions (CMAI), the Consortium on Targeting and Regeneration (CTAR) and the Human Pancreas Analysis Consortium (HPAC). In its first year, HIRN created infrastructure to facilitate interactions and collaborations among this group of scientists. For this purpose, the Human Islet Research Enhancement Center (HIREC), located at City of Hope in Duarte, California, was established. The HIREC ensures that information, data, biomaterials, models, protocols, reagents, resources and methods developed by HIRN Investigators are shared in a timely manner to maximize scientific exchange and help accelerate research in the field.

Consortia

Photo courtesy of: Raghavendra Mirmira, MD, PhD

Consortium on Beta Cell Death and Survival (CBDS)

CBDS uses human tissues to discover highly specific biomarkers of beta cell injury in asymptomatic T1D and developing strategies to stop beta cell destruction early in the disease process.

The signs and symptoms of type 1 diabetes (T1D) — excessive thirst, hunger, tiredness or frequent urination — usually appear very suddenly; new patients are often hospitalized, some with diabetic ketoacidosis, a serious and potentially life-threatening complication. Yet, the disease process that ends with a diagnosis of T1D actually begins months or even years before obvious symptoms occur. This period of "silent" disease development holds important clues to as to why and how beta cells die in T1D and may provide a window of opportunity for stopping the process before the symptoms of diabetes develop. However, research on this period is challenging because the time it takes for the disease to progress to symptoms is highly variable, there is a need for repeated studies of blood samples, and scientists cannot examine the pancreas in living individuals who are at risk for developing T1D because it is located deep within the abdomen.

The Consortium on Beta Cell Death and Survival (CBDS) was created to support new ideas and technologies for studying the silent period of T1D before diagnosis. As but one example of novelty, CBDS members are using new techniques to study single cells or very small groups of cells in the pancreas to find subtle changes in beta cells during the development of diabetes that could be easily missed by looking at large pieces of tissue. Understanding these changes could suggest new treatments to help beta cells survive longer. The consortium is also looking for biomarkers — molecular signs that the beta cells are stressed or dying well before the onset of diabetes symptoms — that could be used as part of a blood test to better identify people who are in the silent period of T1D.

Consortium on Human Islet Biomimetics (CHIB)

Incorporation of human islets into the vascularized micro-organ platform: Confocal imaging of an islet surrounded by vasculature (CD31+, green). DAPI staining (purple) highlights the densely-packed cells in the islets.
Photo Credit: Hugh Bender, Christopher Hughes Lab, Department of Molecular Biology & Biochemistry, University of California, Irvine

CHIB is combining advances in beta cell biology and [Stem_cell|stem cell] biology with tissue engineering technologies to develop microdevices that support functional human islets.

In the human body, pancreatic beta cells are finely tuned, complex machines — they sense how much glucose (sugar) is in a person’s blood and, in response, release exactly as much insulin into the bloodstream as the body needs. Beta cells make this calculation over and over, constantly tweaking their work as glucose levels rise and fall when a person eats, moves, sleeps and generally goes about daily life. A grand challenge in diabetes research is to grow human beta cells in the laboratory that mimic how they work in the body. Scientists have successfully used pluripotent cells (cells with the potential to turn into any cell type in the body) to create cells that make insulin. However, these stem cell derived beta cells are difficult to grow by traditional lab methods and they do not work exactly like beta cells do in the body.

The Consortium on Human Islet Biomimetics (CHIB) was assembled to investigate one of the most important differences between beta cells grown in the lab and beta cells in the human pancreas — the microenvironment. In the lab, cells are usually grown in flat layers without other types of cells, whereas in the body, beta cells are part of a small village of supportive neighbors and services. Beta cells in the pancreas live in three-dimensional "islets" or small clusters with several other types of cells as close neighbors. Blood vessels and nerves weave through the islets like streets, aiding the delivery of food, oxygen, hormones and other signals that help the islet cells grow and work properly. Further, these clusters are housed within 3-D niches that provide mechanical support and deliver signals from the surrounding environment. By recreating the village environment of a human islet in the lab, CHIB scientists hope to turn stem cell-derived beta cells into fully functional beta cells.

Consortium on Modeling Autoimmune Interactions (CMAI)

CMAI is developing innovative approaches to model basic aspects of human T1D immunobiology using novel in vivo and in vitro platforms.

Scientists have known for more than 40 years that type 1 diabetes (T1D) is an autoimmune disease — one in which the immune system, which normally protects the body from bacteria, viruses, and other foreign microbes, mistakenly destroys the body’s own cells. In T1D, the beta cells in the pancreas are destroyed and the body loses its only source of insulin, a hormone that is essential for life. What remains unknown is what starts the autoimmune process in the first place, why the immune system singles out the beta cells for destruction in some people and what role, if any, the beta cells have in triggering this abnormal response from the immune system. Much research has been done to understand T1D autoimmunity in murine models of the disease. While these studies have provided many clues about the disease process, there are important differences between human and animal immune systems and pancreatic islets. The Consortium on Modeling Autoimmune Interactions (CMAI) is focused on studies of human immunity and pancreatic islets by studying human cells and tissues in culture and in "experimental" mice.

The CMAI was established to develop the tools, reagents and resources necessary to build a robust model of the human immune system interacting with genetically matched human islet cells. Ultimately, such models can be used for basic research to unravel the autoimmune process in T1D, as well as for translational research to develop new therapies that stop or reverse the process.

Consortium on Targeting and Regeneration (CTAR)

Title: Converting Adult Pancreatic Islet α Cells into β Cells by Targeting Both Dnmt1 and Arx
Mechanisms maintaining islet a-cell fate remain unclear. Studies by Chakravarthy et alreveal mouse a-cell conversion into b-cells after Dnmt1 and Arx inactivation, suggestingpathways to achieve b-cell regeneration. similar changes in subsets of islets in type 1 diabetes (T1D) suggests a molecular basis for a-cell dysfunction in T1D.

CTAR is investigating methods to increase or maintain functional beta cell mass in T1D through targeted manipulation of islet plasticity or engineered protection of beta cells from immune-mediated destruction.

Every day, millions of people with type 1 diabetes (T1D) or severe type 2 diabetes inject insulin multiple times or use an insulin pump in order to control the levels of glucose (sugar) in their blood. Without enough pancreatic beta cells to produce insulin, these patients depend on daily insulin therapy for life.

The Consortium on Targeting and Regeneration (CTAR) is developing new approaches to diabetes treatment that would free patients from daily insulin therapy — safe, controlled replenishment of working beta cells using the patient’s own cells and tissues. This replenishment — or regeneration — of beta cells could be done by encouraging the few beta cells that remain in some diabetic pancreases to divide and create new copies of themselves. Or, using knowledge gained from pluripotent cells and other avenues of research, nonbeta cell types could be nudged to transform or "reprogram" themselves into new insulin-producing cells. Critically, regenerated beta cells may need to be changed in ways that protect them from the autoimmune process that destroyed the patients' original beta cells.

Human Pancreas Analysis Consortium (HPAC)

Human Pancreas Analysis Consortium (HPAC) is performing deep [Phenotype|phenotyping] of the human endocrine pancreas and its interaction with the immune system to better understand the cellular and molecular events that precede and lead to the beta cell loss in type 1 diabetes (T1D). T1D datasets is provided to the diabetes research community through the HPAP program within the HPAC.

Coordinating Groups

The project is managed with an Administrative Hub consisting of Program Staff at the NIH NIDDK, a Coordinating Center (CC) and a Bioinformatics Center (BC).The project is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Type 1 Diabetes special funding program.

Trans-Network Committee

The Trans-Network Committee (TNC) consists of members of each scientific consortium, the Coordinating Center, Bioinformatics Center, and NIDDK Program Staff.

The committee's responsibilities:

• Facilitate communication and foster collaboration across the different consortia

• Advise during development of the agenda for the yearly HIRN Annual Meeting
• Discuss implementation of HIRN "opportunity pool" funds

Members of the Trans-Network Committee Include:

Alvin Powers, MD Ashu Agarwal, PhD Klaus Kaestner, PhD, MS John Kaddis, PhD Olivier Blondel, PhD Layla Rouse, MS

Lori Sussel, PhD Todd Brusko, PhD Joyce Niland, PhD Kristin Abraham, PhD Sheryl Sato, PhD

Human Islet Research Enhancement Center (HIREC)

The Human Islet Research Enhancement Center (HIREC) is located within the Department of Diabetes and Cancer Discovery Science at City of Hope. It serves as an organizational hub for the Human Islet Research Network (HIRN) addressing the administrative, organizational, and functional needs of the HIRN to understand how human beta cells are lost in Type 1 Diabetes and finding innovative strategies to protect or replace functional beta cell mass in diabetic patients.

HIREC provides investigators with tools, processes, and methods to facilitate long term sharing, maintenance, and management of HIRN developed resources, including datasets, technologies, documents, and bioreagents. Collaboration and communication are cultivated through consultation and outreach activities.

Annual Meetings

An in-person meeting of the members of the Human Islet Research Network (HIRN) is held annually. The meeting consists of scientific sessions, breakout sessions, poster sessions as well as consortium-specific meetings. Attendees include investigators, trainees, NIH staff, Coordinating Center (CC) and Bioinformatics Center (BC) as well as invited guests (i.e. dkNET, Helmsley Charitable Trust, IIDP, JDRF, nPOD and the T1DExchange).