Thu Le
Research Overview
My laboratory studies renal mechanisms of hypertension and genetic determinants of susceptibility to kidney disease progression. Our work spans basic science using mouse models of diseases to translational and clinical research.
Current Projects
Role of GSTM1 deficiency in chronic kidney disease progression. Our work identified that glutathione-S-transferase mu-1 gene, Gstm1, is a candidate gene for renal vascular remodeling in a mouse model. The translational work in my laboratory from mouse to human identified that the common null allele of GSTM1 gene in humans is associated with accelerated kidney disease progression in the African American Study of Hypertension and Kidney Disease (AASK) Trial participants. We have further assessed the joint effects of GSTM1 and APOL1 in AASK, and found that the GSTM1 null allele and APOL1 high risk alleles have independent and additive deleterious effect on the composite outcomes of decline in eGFR, dialysis, and death. A similar effect of GSTM1 null allele was observed in the Atherosclerosis Risk in Communities (ARIC) study in African Americans and European Americans. Importantly, in our study in both humans and mice that received world-wide press release, we showed that Gstm1 knockout mice have worse kidney injury compared to their wild-type littermates, but only the knockout mice derive a kidney protective effect when their diet was supplemented with powder of the cruciferous vegetable broccoli that is rich in sulforaphane. Similarly, we showed in ARIC that while patients with the GSTM1 null allele are more at risk for kidney disease progression and kidney failure, these patients also derive more benefit from high intake of cruciferous vegetables compared to those carrying one or two active GSTM1 alleles. Our work has advanced the conceptual understanding of gene-environment interaction in kidney disease and precision medicine. This work has evolved to an NIH funded clinical trial to test the safety and efficacy of sulforaphane supplement in CKD stages 3-4 in a Phase 2 study. Our lab is currently delineating a metabolic pathway that is modulated by GSTM1 to more precisely identify a therapeutic target for patients who are most genetically at risk for kidney disease progression.
Collectrin (Tmem27) in hypertension and salt-sensitivity. The goal of this project is to define the physiological role of collectrin, Tmem27, a chaperone of amino acid transporters, in blood pressure homeostasis. We previously reported that collectrin, by regulating arginine uptake, regulates nitric oxide and superoxide balance. We will use a tissue-specific knockout approach to delineate the tissue-collectrin-nitric oxide synthase axis and renal mechanisms (tubular epithelial regulation versus renal blood flow) by which collectrin influences blood pressure and the adaptive response to high salt intake. In addition, using a translational approach, we will be the first to comprehensively examine the effect of genetic variants of collectrin on blood pressure in 4 different human populations. In the context of debates in the field of hypertension, our findings may be able to address the decades-old question whether vascular dysfunction in general, and specifically that in the kidney, is a prerequisite for salt sensitivity and/or hypertension.
New Directions
We have also become interested in the relationship between the type of vascular access and the development or progression of right heart dysfunction and pulmonary hypertension in hemodialysis patients. We are proposing a clinical study to examine this relationship. Plan is also underway to develop a mouse model to be able to address this phenomenon mechanistically.
Grants
Renal Mechanisms of Blood Pressure Regulation and Salt Sensitivity by Collectrin
NIH R01 DK113632
08/15/2017 – 05/31/2022
PI (3.0 CM)
Leveraging Ancestry to Map Kidney Loci
NIH R01 MD012765
09/24/2017 – 04/30/2022
Sub-award PI (1.2 CM)
Genetics of kidney disease in diverse populations
NIH R01 DK117445-01
09/01/2018 – 08/30/2023
Sub-award PI (1.2 CM)
GSTM1, APOL1, and their joint contribution to severity of Hypertension and chronic kidney disease
NIH R01DK094907-07
06/01/2019 – 05/31/2022
PI (1.2 CM)
New Signaling Networks in Vascular Smooth Muscle
NIH R01HL147555
07/01/2019 – 06/31/2024
Sub-award PI (1.2 CM)
Safety, Feasibility and Efficacy of Sulforaphane in Chronic Kidney Disease (CKD). This is a Phase 2 randomized double blind placebo control trial to determine the safety and efficacy of sulforaphane in patients with CKD Stages 3 and 4
NIH R01 DK128677
9/01/2021–03/31/2024
PI (3.0 CM)
Lab Members
- Luojing Chen, PhD, Research Assistant Professor
- Yves T. Wang, PhD, Staff Scientist
- Tim Beane, Technical Associate II
- Jason Cunningham, Lab Tech III
Publications
Full list of publications
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