Grant: Pr. Gr.- PA: Sex/Gender in Health Res.- Understanding sex/gender mech./processes
Ottawa Hospital Research Institute
$100,000.00
Cellular and molecular pathogenesis of renal tuberous sclerosis complex
FY 2024-25
Summary
Tuberous Sclerosis Complex (TSC) is a disease that affects more than two million people. TSC is caused by mutations in crucial proteins known as TSC1 and TSC2 that lead to abnormal growths or lesions in many tissues. About 80% of TSC patients have kidney disease, which includes cysts and a lesion known as renal angiolipoma (R-AML), which is a leading cause of chronic kidney disease and mortality due to TSC. Only one drug is available to slow TSC progression, but it does not kill TSC cells and many patients fail to respond. Patients with TSC need new therapies that will kill the dangerous lesions. However, to discover and test new TSC drugs, we first need effective cell and animal models of TSC.
We have made great strides in this work. We made human TSC stem cell models and used them to make mini-kidneys that develop cysts and display many characteristics of R-AML in a culture dish and all the characteristics of R-AML when transplanted into mouse kidneys. Using these mini-TSC kidneys, we identified cells from the nervous system that contribute to R-AML formation and confirmed this finding using human TSC surgical specimens. We developed the first genetic mouse model that captures aspects of R-AML. We also used our TSC stem cell models to discover new drugs that kill TSC cells grown in culture dishes and grown in a TSC mouse model.
Now, we propose to perform three studies in parallel. In the first study, we will assess the different cell types that contribute to TSC kidney disease using our mini-kidney model and patient cells transplanted into mouse kidneys. This transplantation model will also be used for drug testing. In studies 2 and 3, we will use complementary mouse models of TSC that we developed to map the developmental origin of TSC kidney disease, learn about lesion growth and whether the lesions will migrate to other tissues. This project will reveal the cells and molecules that drive TSC kidney disease, critical knowledge to develop new therapies.
Department
Program
Pr. Gr.- PA: Sex/Gender in Health Res.- Understanding sex/gender mech./processes
Recipient
Location
Ontario, Canada
Recipient Type
Other
Type
Grant
Source
CIHR Funding Decisions Database
As published
Id
528366
Name
Stanford William L
Region
Ontario
Country
Canada
Orgtype
Institution Paid; Research Institution
Instname2
Gender and Health
Theme2
Biomedical
Prcname2
Hematology, Digestive Disease & Kidney
Projecttitle
Cellular and molecular pathogenesis of renal tuberous sclerosis complex
Programtype2
Operating Grants
Orgnameinp2
Ottawa Hospital Research Institute
Cihramount2
$100,000
Cihrequipment2
$0
Programname2
Pr. Gr.- PA: Sex/Gender in Health Res.- Understanding sex/gender mech./processes
Keyworddelim
Chronic Kidney Disease; Cystogenesis; Human Pluripotent Stem Cells; Mouse Models Of Disease; Renal Angiomyolipoma; Renal Organoids; Single-Cell Omics; Tuberous Sclerosis Complex; Xenograft Models
Abstract
Tuberous Sclerosis Complex (TSC) is a disease that affects more than two million people. TSC is caused by mutations in crucial proteins known as TSC1 and TSC2 that lead to abnormal growths or lesions in many tissues. About 80% of TSC patients have kidney disease, which includes cysts and a lesion known as renal angiolipoma (R-AML), which is a leading cause of chronic kidney disease and mortality due to TSC. Only one drug is available to slow TSC progression, but it does not kill TSC cells and many patients fail to respond. Patients with TSC need new therapies that will kill the dangerous lesions. However, to discover and test new TSC drugs, we first need effective cell and animal models of TSC.
We have made great strides in this work. We made human TSC stem cell models and used them to make mini-kidneys that develop cysts and display many characteristics of R-AML in a culture dish and all the characteristics of R-AML when transplanted into mouse kidneys. Using these mini-TSC kidneys, we identified cells from the nervous system that contribute to R-AML formation and confirmed this finding using human TSC surgical specimens. We developed the first genetic mouse model that captures aspects of R-AML. We also used our TSC stem cell models to discover new drugs that kill TSC cells grown in culture dishes and grown in a TSC mouse model.
Now, we propose to perform three studies in parallel. In the first study, we will assess the different cell types that contribute to TSC kidney disease using our mini-kidney model and patient cells transplanted into mouse kidneys. This transplantation model will also be used for drug testing. In studies 2 and 3, we will use complementary mouse models of TSC that we developed to map the developmental origin of TSC kidney disease, learn about lesion growth and whether the lesions will migrate to other tissues. This project will reveal the cells and molecules that drive TSC kidney disease, critical knowledge to develop new therapies.
Competitiondate
202503
Approvedterm2
1 yr 0 mth
Pinamesdelim
Stanford, William L
Approvedterm
1 an 0 mois
Cihrcontribution2
~ $100,000~ $0~
