First comprehensive genetic blueprint of a forming mammalian organ



In the quest to develop the next generation of anti-infective medicine, Griffith University and Pfizer, the world’s largest research-based pharmaceutical company, announced a leading partnership today. Griffith University’s Eskitis Institute for Cell and Molecular Therapies investigates novel drug- and cell-based therapies for human diseases in the areas of cancer, infection and immunity, neglected diseases,

Full Post: Griffith University and Pfizer in new partnership to unlock nature’s cure for infections

Researchers have generated the first comprehensive genetic blueprint of a forming mammalian organ, shedding light on the genetic and molecular dynamics of kidney development.

Part of an international consortium sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a research team led by Cincinnati Children’s Hospital Medical Center reports the creation of a detailed genome-based atlas for understanding healthy and abnormal kidney development and disease. Published in the Nov. 11 Developmental Cell and featured on the journal’s cover, the research provides a molecular genetic map detailing “gene expression analysis of all the major elements of kidney formation,” according to the investigators.

The study, involving embryonic mice, shows how the entire genome is regulated to produce thousands of specific genes that are mixed and re-mixed to form genetic teams. The teams work together to direct formation of 15 embryonic compartments in the developing kidney - from the earliest phases when stem cells are told how to differentiate into specific kidney cells to the development of nephrons, the kidney’s primary functioning unit.

“This study establishes a baseline for what changing gene expression looks like in a normal developing kidney in a very global way,” said Steven Potter, Ph.D., a researcher in the division of Developmental Biology at Cincinnati Children’s and the study’s senior author. “Now we have molecular insights that will allow us to understand specific interactions throughout all stages of kidney development.”

Dr. Potter explained this will let researchers analyze kidney abnormalities in mutant mice “in a much more complete and profound way than ever before. Given the mouse’s genetic similarities with people, this should help us understand the underpinnings of human disease,” he said.

The researchers conducted their multi-step analysis of mouse embryonic kidneys that were aged 15.5 days. This developmental time point in a mouse’s normal 19- to 21-day gestation allows multiple stages of kidney formation to be studied at once because of how the organ develops. The organ’s outer layers contain early stem cells that are still differentiating to become specific cell types, while inside the organ structures are forming at intermediate and more mature stages. This enabled measurement of varied gene expression stage-by-stage, compartment by compartment, the researchers said.

One of the study’s more unexpected discoveries is overlapping gene expression between the kidney’s different structures, according to Eric Brunskill, Ph.D., the study’s lead author. Most of the thousands of genes involved in making a mammalian kidney are expressed at some level in every compartment. Previously it had been thought each kidney compartment would have unique genes driving its development, and those genes would not be expressed in the cells of other structures. This is not the case, as the research team found only a small number of genes expressed exclusively in specific kidney structures.

“Instead of it being a digital on-off pattern, where you might have many unique genes expressed in one part of the kidney but not in the other structures, we instead see a more analog picture, where almost all of the genes are expressed in the different parts but at varied levels,” Dr. Brunskill said.

Helping make this discovery possible is the study’s use of microarray technology to measure relative expression levels of every gene in each unique structure and developmental stage. Combined with two other technologies to precisely isolate specific types of cell populations (laser capture micro-dissection and florescent activated cell sorting), microarray analysis allowed a more quantitative and sensitive measure of varied gene expression than ever observed in a developing organ system.

Computational biology analysis (bioinformatics) then let the researchers see how different sets of genes cooperate through circuits or pathways, some already defined and others defined in this study for the first time. The genes cooperate by signaling each other, telling cells when to grow, when to make tubes, when to turn on pumps or perform other critical functions, said Bruce Aronow, Ph.D., study co-author and scientific director of the Center for Computational Medicine at Cincinnati Children’s. The study also makes new headway into identifying different transcription factors - “boss” genes that regulate the activity of other genes - and the target genes they may activate or repress.

Given that about one in every 500 births results in a kidney development abnormality, this provides insight into genetic programs that are critical to deciding how kidney stem cells form structures in the adult kidney. The researchers identified genes that regulate DNA transcription, establish functioning developmental processes, and are involved in pattern specification, cell differentiation and organ compartment shaping.

http://www.cincinnatichildrens.org/

Link




An international team of researchers, which included scientists from the University of Queensland, have generated an atlas of genes involved in kidney formation. This first comprehensive genetic blueprint of a developing mammal organ, will throw light on the genetic and molecular dynamics of kidney formation and help scientists understand how developmental abnormalities occur and how

Full Post: New genetic kidney atlas will explain kidney disease



To decipher how cancer develops, Johns Hopkins Kimmel Cancer Center investigators say researchers must take a closer look at the packaging. Specifically, their findings in the December 2, 2008, issue of PLoS Biology point to the three dimensional chromatin packaging around genes formed by tight, rosette-like loops of Polycomb group proteins (PcG). The chromatin packaging,

Full Post: Chromatin packaging helps decipher how cancer develops



There are more than 76,000 end-stage renal disease patients waiting for one of the 17,000 kidneys transplanted each year, making a host rejection an unacceptable waste. Kidney transplantation is the preferred treatment for patients with end-stage renal disease. As the demand for organs exceeds the supply, blood group (ABO)-incompatible kidney transplantations have gained much importance

Full Post: Humoral immunity in kidney transplantation



A multidisciplinary research team at Case Western Reserve University led by Gary Landreth, Ph.D., a professor in the School of Medicine’s Department of Neurosciences, has uncovered a common genetic pathway for a number of birth defects that affect the development of the heart and head. Abnormal development of the jaw, palate, brain and heart are

Full Post: Researchers discover genetic basis for some common congenital birth defects



Human calmodulin-like protein (CLP) is found in many cell types including breast, thyroid, prostate, kidney, and skin. The protein can regulate many cell activities and has a highly specific expression. Gaining an understanding about the expression of CLP in oral epithelial cells and its possible downregulation (or lack of production) in cancer may be a

Full Post: Lack of human calmodulin-like protein can be indicative of oral cancer