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Madhav Menon, MBBS, MD

Associate Professor
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Additional Titles

Director of Research in Kidney Transplantation, Nephrology

Steering committee member, Human and Translational Immunology Program

About

Titles

Associate Professor

Director of Research in Kidney Transplantation, Nephrology; Steering committee member, Human and Translational Immunology Program

Appointments

Education & Training

Fellowship
Recanati-Miller Transplant institute at Mount Sinai (2014)
Post doctoral Fellowship
Icahn School of Medicine at Mount Sinai (2013)
Fellowship
Icahn School of Medicine at Mount Sinai (2012)
Residency
State University of New York, Upstate Medical University (2010)
Chief Residency
PGIMER (2006)
MD
PGIMER, Internal Medicine (2006)
MBBS
Calicut University (2002)

Research

Overview

 1. By histology in native and allograft kidneys, CKD is characterized by renal interstitial fibrosis, vascular intimal fibrosis and glomerulo- sclerosis, reflecting damage to different renal compartments.  We previously showed that a CKD-associated SHROOM3 SNP - Rs17319721, in the donor kidney increased SHROOM3 expression (by TCF7L2-dependent transcription) and promoted renal allograft fibrosis (IF/TA), through TGF-β1 signaling. These data contrast with evidence of a protective role for Shroom3 in glomerular development and association of this SNP with reduced albuminuria. To study mechanism of these dichotomous effects, we have developed inducible Shroom3 knockdown mice and observed reduced renal fibrosis with non-glomerular Shroom3 knockdown. Conversely, glomerular-, but not tubular-Shroom3 knockdown, induced albuminuria with diffuse podocyte foot process effacement without podocyte loss. In podocytes, we identified a new interaction of SHROOM3 with FYN (a Src kinase) via a critical Src homology-3 binding domain, distinct from its established domains. In vitro and in vivo, Shroom3-Fyn interaction was required for activation of Fyn kinase and downstream Nephrin phosphorylation and actin cytoskeleton in podocytes and explains the protective effect of Shroom3 on proteinuria. We are testing the dichotomous roles of Shroom3 in renal tubular cells and podocytes, that are mediated by distinct protein motifs. We have generated  ASD2- domain deficient Shroom3 mutants to confirm ASD2-domain dependent profibrotic signaling by Shroom3, while Fyn-binding mutant Shroom3 will be overexpressed to confirm podocyte injury and phenotype in vivo.  This work is focused on targeting Shroom3  for fibrosis in CKD and IF/TA.

2. Podocyte AMPK-signaling- Translating discoveries to humans: The phenotype of Shroom3 knockdown is similar to human minimal change disease (MCD) which has good prognosis vs FSGS (podocyte loss and sub-optimal prognosis). Since impaired Fyn activation is associated with human  MCD, and Shroom3 knockdown inhibited Fyn , we evaluated whether collateral signaling mechanisms downstream of Fyn  promoted podocyte survival. We identified enhanced AMPK-activation downstream of Shroom3-Fyn as a key prosurvival mechanism. Based on the widely used and safe AMPK-activator Metformin, and our mechanistic our group has designed a RCT (clinical trial) to test  utility of Metformin  to promote podocyte survival in FSGS. Analogously unique mouse models have been developed to understand mechanisms of podocyte survival downstream  of AMPK including autophagy.

3. APOL1 variants and kidney injury: While Americans of African ancestry make up 13% of the United States, they account for 35% of kidney failure. This is attributed to the carriage of risk alleles in APOL1 (referred to G1/G2 risk alleles). Unfortunately, those with APOL1 risk variants manifest with FSGS, which is the most common form of nephrotic syndrome. However, limited mechanistic understanding of this disease process has hindered novel treatments, especially due to the lack of suitable animal models for study. With Dr Ishibe, we have a mouse model that expresses human APOL1 risk alleles. Upon stimulation with an inflammatory agent, these mice develop excessive protein loss in the urine resembling human FSGS. Using data in humans, we identified for the first time that immune cells, in addition to kidney cells, may play a profound role in disease processes including kidney transplant rejection. We propose that specific immune cells in individuals with G1/G2 APOL1 damage the kidney filtration barrier (in native kidneys) or promote rejection (in transplants). We focus on studying APOL1-variant carrying T-cells using invivo/invitro tools to understand their role as upstream effectors of kidney disease and allo-immunity.

 2. Non HLA-mismatches and renal allograft failure: Recent data has shown that focal or global non-HLA donor-recipient mismatches associate with renal allograft outcomes. Here we examined global non-HLA mismatches by quantifying these in every donor-recipient pair in a scale of 0-1 using proportion of identity-by-descent (piBD). We showed that such a score independently associates with allograft survival via the development of early allograft fibrosis especially vascular intimal lesions or Cv-score.  Based on these data, (a) we are applying bioinformatic approaches to dissect loci and regions of interest (b) identify potential implicated mechanisms based on genetic architecture (c) validate using a murine model of global non MHC mismatches. This work has significant implications for allocation, risk stratification and potential targeted therapeutics. We identify novel mechanisms by which donor-recipient "mismatches" impact transplant outcomes. One such leading candidate is the region of LIMS1-GCC2 on chromosome 2, where complex mechanisms involving gene expression regulation underlie association of specific loci with graft loss.

Research at a Glance

Yale Co-Authors

Frequent collaborators of Madhav Menon's published research.

Publications

2024

2023

Clinical Trials

Current Trials

Academic Achievements & Community Involvement

  • activity

    Agence nationale de la recherche, France

  • activity

    Clinical Transplantation, Wiley Publishers

  • activity

    Dutch Kidney Foundation

  • activity

    American society of Nephrology

  • activity

    NIH NIAID Study section

Clinical Care

Overview

Clinical Specialties

Nephrology

Fact Sheets

Board Certifications

  • Nephrology

    Certification Organization
    AB of Internal Medicine
    Latest Certification Date
    2023
    Original Certification Date
    2012
  • Internal Medicine

    Certification Organization
    AB of Internal Medicine
    Latest Certification Date
    2023
    Original Certification Date
    2010

Yale Medicine News

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Contacts

Appointment Number

Administrative Support

Locations

  • The Anlyan Center

    Lab

    300 Cedar Street, Ste S240

    New Haven, CT 06519